Bispecific T Cell Engager BRiTE for Patients With Grade IV Malignant Glioma

This phase 1 study will evaluate a novel hEGFRvIII-CD3-biscFv Bispecific T cell engager (BRiTE) in patients diagnosed with pathologically documented World Health Organization (WHO) grade 4 malignant glioma (MG) with an EGFRvIII (epidermal growth factor receptor variant III) mutation (either newly diagnosed or at first progression/recurrence). The primary objective is to evaluate the safety of BRiTE in such patients.

A maximum of 18 patients with pathologically documented supratentorial WHO grade 4 malignant glioma with an EGFRvIII mutation (either newly diagnosed or at first progression/recurrence) will be treated in this study after undergoing standard of care radiation therapy (XRT) and providing informed consent. After completion of a minimum of 6 cycles of adjuvant temozolomide (TMZ), or at first progression, eligible patients will receive a bolus BRiTE injection followed by a 28-day safety monitoring period. Blood will be drawn to assess the pharmacokinetics (PKs) of BRiTE injection, as well as to investigate the immune system response to BRiTE injection and evaluate for cytokine release syndrome (CRS). Following the 28-day monitoring period, patients will be passively followed as part of their standard of care follow-up.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years old
* Pathologically documented supratentorial WHO grade IV malignant glioma with an EGFRvIII mutation confirmed by Caris (at most recent diagnosis)

  1. If patient is newly diagnosed, the patient must have completed standard of care radiation therapy (3 or 6 week courses are accepted) with or without temozolomide:

     Patients with methylated MGMT promoter status need to initiate or complete 6 cycles of adjuvant temozolomide to be eligible.

     Patients with an unmethylated MGMT promoter status do not need to initiate or complete adjuvant temozolomide to be eligible
  2. If patient is at first progression, the patient must have radiographic evidence of progression and completed a standard of care regimen of radiation therapy with or without chemotherapy and initiated adjuvant chemotherapy. Note: Imaging must be completed within 14 days of enrollment.
  3. Patients who progress during XRT or within 4 weeks after completion of XRT are not eligible.
* Karnofsky Performance Score (KPS) ≥ 70%
* Absolute neutrophil count (ANC) ≥ 1000/mm3
* Platelet count ≥ 100,000
* Hemoglobin ≥ 9.0 g/dL
* Creatinine ≤ 1.2 x normal range
* Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT) ≤ 2.5 x ULN
* Total bilirubin ≤ 2 x ULN (Exception: Patient has known Gilbert's Syndrome or patient has suspected Gilbert's Syndrome, for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.))
* For women of childbearing potential: negative serum pregnancy test within 1 week of 1st BRiTE injection.

Exclusion Criteria:

* Women who are pregnant of breastfeeding
* History or evidence of central nervous system bleeding as defined by stroke or intraocular bleed (including embolic stroke) not associated with any antitumor surgery within 6 months before enrollment
* Known hypersensitivity to immunoglobulins or to any other component of the BRiTE
* Prior malignancy (other than in situ cancer) unless treated with curative intent and without evidence of disease for \> 2 years before screening
* Infection requiring intravenous antibiotics that was completed \< 1 week of study enrollment (day 1) with the exemption of prophylactic antibiotics for long line insertion or biopsy
* Known positive test for human immunodeficiency virus (HIV)
* Known active hepatitis B or C infection
* Toxicities from prior antitumor therapy have not resolved to CTCAE version 5 grade 1 (with the exception of adverse events reflecting myelosuppression such as neutropenia, anemia, or thrombocytopenia), or to levels dictated in the eligibility criteria. Exceptions include: alopecia or toxicities from prior antitumor therapy that are considered irreversible (defined as having been present and stable for \> 2 months) are allowed if they are not otherwise described in the exclusion criteria
* Patients on corticosteroids ≥ 2 mg dexamethasone daily or equivalent within 14 days of 1st BRiTE injection
* Females of reproductive potential and males who are unwilling to practice an acceptable method(s) of effective birth control while on study through 1 week (5 half-lives) after receiving the last dose of study drug