Bispecific T Cell Engager BRiTE for Patients With Grade IV Malignant Glioma
Study Details
Study Description
Brief Summary
This is a phase 1 study of hEGFRvIII-CD3-biscFv Bispecific T cell engager (BRiTE) in patients diagnosed with World Health Organization (WHO) grade IV malignant glioma (MG). The primary objective is to evaluate the safety of BRiTE alone and in combination with peripheral autologous T-cell infusion in patients whose MG has an EGFR (epidermal growth factor receptor) variant III (EGVRvIII) mutation.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
A maximum of eighteen patients will participate in this study after undergoing undergoing standard of care radiation therapy (XRT) with or without concomitant temozolomide (TMZ). Patients will undergo a leukapheresis to generate autologous lymphocytes that may be infused prior to BRiTE injection, pending tolerance of the BRiTE only injection. For newly diagnosed patients, leukapheresis will occur either before initiating radiation therapy or after completing radiation therapy, but before initiating adjuvant temozolomide. After completion of a minimum of six cycles of adjuvant temozolomide, or at first progression, eligible patients will receive a bolus BRiTE injection followed by a 14-day safety monitoring period. If no dose limiting toxicity (DLT) or unacceptable toxicity occurs within 14 days, patients will receive an infusion of activated cell therapy (ACT) derived from autologous lymphocytes immediately followed by a second bolus BRiTE injection.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: hEGFRvIII-CD3 (BRiTE) with and without peripheral autologous T-cell (ACT) infusion Four escalating doses of BRiTE are planned: #1: 57.0 ng/kg, #2: 570.0 ng/kg, #3: 5700.0 ng/kg, and #4: 57000.0 ng/kg. With the second injection of BRiTE, patients will each receive 3 x 10^7 T-cells per kg. |
Drug: hEGFRvIII-CD3 (BRiTE)
Bispecific T cell engager possessing one effector binding arm specific for the epsilon subunit of CD3 (a signaling molecule complex associated with the T cell receptor on T cells) while the opposing target-binding arm is directed against the hEGFRvIII epitope that is differentially expressed on the surface of tumor cells
Other Names:
Biological: Activated Cell Therapy
Autologous activated human T cells obtained via leukapheresis
Other Names:
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Outcome Measures
Primary Outcome Measures
- Dose-limiting toxicity (DLT) [Begins when first BRiTE injection is given and goes through 28 days after the 2nd BRiTE injection]
Proportion of patients with DLT within each dose level
Secondary Outcome Measures
- Objective response rate (ORR) [7 weeks]
ORR per modified Response Assessment in Neuro-Oncology Criteria (RANO)
- Pharmacokinetic (PK) of BRiTe observed during the first injection of BRiTE as measured by time (in minutes) [96 hours post BRiTE injection]
Time for the concentration of BRITE to reach half of the level initially administered
- Pharmacokinetic (PK) of BRiTe administered with ACT as measured by time (in minutes) [96 hours post BRiTE injection]
Time for the concentration of BRITE to reach half of the level initially administered
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥ 18 years old
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Pathologically documented supratentorial WHO grade IV malignant glioma with an EGFRvIII mutation confirmed by Caris (at most recent diagnosis)
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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. i. Patients with methylated MGMT promoter status need to initiate or complete 6 cycles of adjuvant temozolomide to be eligible. ii. Patients with an unmethylated MGMT promoter status do not need to initiate or complete adjuvant temozolomide to be eligible
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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.
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Patients who progress during XRT or within 4 weeks after completion of XRT are not eligible.
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Karnofsky Performance Score (KPS) ≥ 70%
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Absolute neutrophil count (ANC) ≥ 1000/mm3
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Platelet count ≥ 100,000
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Hemoglobin ≥ 9.0 g/dL
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Creatinine ≤ 1.2 x normal range
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Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
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Alanine aminotransferase (ALT) ≤ 2.5 x ULN
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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.))
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For women of childbearing potential: negative serum pregnancy test within 1 week of 1st BRiTE injection.
Exclusion Criteria:
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Women who are pregnant of breastfeeding
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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
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Known hypersensitivity to immunoglobulins or to any other component of the BRiTE
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Prior malignancy (other than in situ cancer) unless treated with curative intent and without evidence of disease for > 2 years before screening
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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
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Known positive test for human immunodeficiency virus (HIV)
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Known active hepatitis B or C infection
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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
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Patients on corticosteroids ≥ 2 mg dexamethasone daily or equivalent within 14 days of 1st BRiTE injection
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
Sponsors and Collaborators
- Duke University
Investigators
- Principal Investigator: Mustafa Khasraw, MBChB, MD, FRCP, FRACP, Duke University
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- Pro00108079