EGFR Bispecific Antibody Armed T cells in Combination with Radiation Therapy and Temozolomide in Treating Participants with Newly Diagnosed Glioblastoma
This phase I trial studies the side effects and best dose of EGFR bi-armed autologous T cells in combination with radiation therapy and temozolomide in treating participants with newly diagnosed glioblastoma. EGFR bi-armed autologous T cells target the EGFR molecules on glioblastoma tumor cells and use the body's own immune system to destroy those tumor cells. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving EGFR bi-armed autologous T cells with radiation therapy and temozolomide may work better in treating participants with newly diagnosed glioblastoma.
Inclusion Criteria
- Histologically-confirmed newly diagnosed intracranial GBM or gliosarcoma.
- Karnofsky performance status (KPS) >= 60.
- Be willing and able to provide written informed consent for the trial.
- Main study: Planning to undergo or has undergone tumor resection (partial or gross total). Unmethylated cohort: Planning to undergo or has undergone tumor resection or biopsy (in cases where tumor resection is contraindicated).
- Computed tomography (CT)/magnetic resonance imaging (MRI) with contrast must be performed within 72 hours following resection. Intraoperative post resection MRI is acceptable.
- Females of childbearing potential, and males, must be willing to use an effective method of contraception.
- Females 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.
- Unmethylated cohort only: MGMT unmethylated per University of Virginia (UVA) Pathology
- Absolute lymphocyte count >= 500/mm^3 within 10 days prior to apheresis.
- Absolute neutrophil count (ANC) >= 1,000 /mcL within 10 days prior to apheresis.
- Platelets >= 100,000 / mcL within 10 days prior to apheresis.
- Hemoglobin >= 9 g/dL (or >= 5.6 mmol/L without transfusion within 10 days prior to apheresis or erythropoietin (EPO) dependency (within 7 days of assessment).
- Blood urea nitrogen (BUN) =< 1.5 X upper limit of normal (ULN) within 10 days prior to apheresis.
- Serum creatinine within normal limits OR measured or calculated creatinine clearance (CrCl) >= 60 mL/min/1.73 m^2 within 10 days prior to apheresis. (Glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl). * Creatinine clearance should be calculated per institutional standard.
- Serum total bilirubin within 10 days prior to apheresis =< 1.5 X ULN. OR
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X ULN within 10 days prior to apheresis.
- Albumin >= 2.5 mg/dL within 10 days prior to apheresis.
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants within 10 days prior to apheresis.
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants within 10 days prior to apheresis.
Exclusion Criteria
- Patients with a diagnosis of another malignancy within 3 years of being on-study. 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. Patients must not be on any treatment for another malignancy.
- Patients with evidence of leptomeningeal dissemination or subependymal spread on initial MRI.
- Patients with extracranial metastases.
- Known hypersensitivity to cetuximab or other EGFR antibody.
- Alpha 1,3 galactose IgE (“alpha gal”) test result outside of the reference range (indicating likely hypersensitivity to cetuximab).
- Evidence of active bleeding or bleeding diathesis.
- Cardiac status: patients will be ineligible for treatment on this protocol if (prior to protocol entry): * There is a history of a recent (within one year) myocardial infarction or stroke. * There is a current or prior history of angina/coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by multigated acquisition scan [MUGA] or echocardiography [ECHO]). * There is clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA or ECHO results).
- Has human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).
- Has received a live vaccine within 30 days of planned start of study therapy.
- Has received any treatment for GBM besides surgery.
- Females must not be breastfeeding.
- 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.
- A patient may be excluded if, in the opinion of the treating clinician, the patient is not capable of being compliant.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03344250.
PRIMARY OBJECTIVE:
I. Determine the maximum tolerated dose (MTD) of adding EGFR bi-armed activated T cells (EGFR BATs) therapy to radiation and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM).
SECONDARY OBJECTIVES:
I. Measure immune responses by sequential monitoring of cellular phenotype, interferon-gamma (IFN-gamma), enzyme-linked immunospot assays (EliSpots), anti-GBM cytotoxicity of peripheral blood mononuclear cells (PBMC) directed at GBM cell lines, serum cytokine patterns, and anti-glioma antibodies in the serum during the “induction and consolidation” stages of GBM treatment.
II. Preliminary assessment of response rate, progression-free survival (PFS) and overall survival (OS).
III. Correlate individually and by heatmap analysis, imaging (extent of resection), pathology (EGFR expression and tumor-infiltrating lymphocytes [TIL]), clinical (steroid use at the time of leukapheresis and age), and immune response characteristics to PFS and OS.
IV. Confirm the safety of 8 weekly doses of EGFRBi-armed T cells (EGFR BATs) therapy (combined total dose = 80 x 10^9 cells) alone following combined radiation treatment (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) and unmethylated MGMT status. (Unmethylated MGMT Without Adjuvant TMZ cohort only)
OUTLINE: This is a dose escalation trial of EGFR bi-armed autologous T cells.
MAIN STUDY: Participants undergo standard of care radiation therapy (RT) for 5 days per week and TMZ orally (PO) on days 1-7 for 6 weeks. Participants receive EGFR bi-armed autologous T cells intravenously (IV) over 15-30 minutes on days 14 and 21 after completion of RT/TMZ. Participants then receive EGFR bi-armed autologous T cells IV on day 21 and TMZ PO on days 1-5. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MGMT-UNMETHYLATED SUB-COHORT: Participants with MGMT unmethylated GBM undergo standard of care RT for 5 days per week and temozolomide PO on days 1-7 for 6 weeks. Participants then receive EGFR bi-armed autologous T cells IV weekly for 8 weeks starting 3-6 weeks after completion of RT/TMZ. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days, then every 3 months thereafter.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of Virginia Cancer Center
Principal InvestigatorCamilo Enrique Fadul
- Primary ID20105
- Secondary IDsNCI-2018-01762, EGFR BATS
- ClinicalTrials.gov IDNCT03344250