Phase I EGFR BATs in Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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This is a phase I trial using EGFR Bi-armed Activated T-cells (BATs) in combination with standard of care temozolomide (TMZ) and radiation (RT) in patients with glioblastoma (GBM). The purpose of the study is to determine a safe dose of EGFR BATs when given with standard of care therapy.

Detailed Description
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In addition to finding the safe dose of EGFR BATs, immune evaluations will be performed as delineated in the schedule of events to measure immune responses during all stages of treatment for GBM.

Official Title
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A Phase I Study Targeting Newly Diagnosed Glioblastoma With Anti-CD3 × Anti-EGFR Bispecific Antibody Armed T Cells (EGFR BATs) in Combination With Radiation and Temozolomide

Conditions
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Glioblastoma, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: EGFR BATs with TMZ following SOC RT/TMZ
* Drug: Weekly EGFR BATs following SOC RT/TMZ


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed newly diagnosed intracranial GBM or gliosarcoma Age ≥ 18 years. Karnofsky Performance Status ≥ 60. Be willing and able to provide written informed consent for the trial. For patients with resection, CT/MRI with contrast must be performed within 72 hours following resection. Intraoperative post resection MRI is acceptable. No post surgery CT/MRI is required for patients who have received biopsy. 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. Demonstrate adequate organ function as defined below. All screening labs should be performed within 10 days prior to apheresis. Absolute lymphocyte count ≥ 500/mm3, Absolute neutrophil count (ANC) ≥1,000 /mcL, Platelets ≥ 100,000 / mcL, Hemoglobin ≥ 9 g/dL (or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment), BUN ≤ 1.5 X upper limit of normal (ULN), Serum creatinine within the normal limits OR Measured or calculated creatinine clearance ≥60 mL/min/1.73m2, Serum total bilirubin ≤ 1.5 X ULN OR AST (SGOT) and ALT (SGPT) ≤ 5 X ULN, Albumin >2.5 mg/dL, 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 i. Additional inclusion criteria for sub-cohort: MGMT unmethylated according to UVA pathology testing 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 MUGA or 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: EGFR BATs administered in combination with standard of care temozolomide and radiation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main Study<br>Study participants will have cells collected by leukapheresis prior to initiating standard concurrent RT and TMZ. Participants will receive the first and second infusions of EGFR BATs on days 14 and 21 after finishing concurrent RT and TMZ and then receive an infusion on day 21 of the first six cycles of TMZ. | Drug: EGFR BATs with TMZ following SOC RT/TMZ<br>* Standard of care: 6 weeks of RT and TMZ and 6 cycles of TMZ (150-200 mg/m2) on days 1-5 of each 28 day cycle Experimental: EGFR BATs 2 and 3 weeks after completing RT, and then on day 21 of each cycle of TMZ.<br>|
| Experimental: Subcohort for MGMT unmethylated patients<br>Study participants will have cells collected by leukapheresis prior to initiating standard concurrent RT and TMZ. About 4 weeks after completion of RT/TMZ, participants will receive 8 weekly doses of EGFR BATs. | Drug: Weekly EGFR BATs following SOC RT/TMZ<br>* Standard of care: 6 weeks of RT and TMZ Experimental: 8 weekly doses of EGFR BATs following SOC RT and TMZ<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Maximum tolerated dose will be based on number of dose limiting toxicities at each dose level | The study will not advance to the next dose until 7 days after the last patient in the cohort completes his or her second infusion of EGFR BATs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune measures in blood- cellular phenotype | Sequential monitoring of cellular phenotype | Before surgery (optional), during screening, at apheresis, at multiple timepoints during study treatment, following completion of study treatment, and every 2-6 months after completion of EGFR BATs infusions through 1 year after last EGFR BATs infusion | 
| Immune measures in blood- interferon-γ | Sequential monitoring of interferon-γ | Before surgery (optional), during screening, at apheresis, at multiple timepoints during study treatment, following completion of study treatment, and every 2-6 months after completion of EGFR BATs infusions through 1 year after last EGFR BATs infusion | 
| Immune measures in blood- EliSpots | Sequential monitoring of EliSpots | Before surgery (optional), during screening, at apheresis, at multiple timepoints during study treatment, following completion of study treatment, and every 2-6 months after completion of EGFR BATs infusions through 1 year after last EGFR BATs infusion | 
| Immune measures in blood- anti-GBM cytotoxicity of peripheral blood mononuclear cells directed at GBM cell lines | Sequential monitoring of anti-GBM cytotoxicity of peripheral blood mononuclear cells directed at GBM cell lines | Before surgery (optional), during screening, at apheresis, at multiple timepoints during study treatment, following completion of study treatment, and every 2-6 months after completion of EGFR BATs infusions through 1 year after last EGFR BATs infusion | 
| Immune measures in blood- serum cytokine patterns | Sequential monitoring of serum cytokine patterns | Before surgery (optional), during screening, at apheresis, at multiple timepoints during study treatment, following completion of study treatment, and every 2-6 months after completion of EGFR BATs infusions through 1 year after last EGFR BATs infusion | 
| Immune measures in blood- anti-GBM antibodies | Sequential monitoring of anti-GBM antibodies | Before surgery (optional), during screening, at apheresis, at multiple timepoints during study treatment, following completion of study treatment, and every 2-6 months after completion of EGFR BATs infusions through 1 year after last EGFR BATs infusion | 
| Clinical response | Progression-free survival (PFS) | Every 3 months following last study visit until death or study closure, expected within 5 years | 
| Survival | Overall Survival (OS) | Every 3 months following last study visit until death or study closure, expected within 5 years | 
| Response Rate | Objective Response Rate | Every 3 months following last study visit until death or study closure, expected within 5 years | 
| Correlation of imaging to PFS and OS | Imaging (extent of resection) will be evaluated for correlation with PFS and OS. | Up to 12 months after study treatment completion | 
| Correlation of pathology to PFS and OS | EGFR expression and tumor-infiltrating lymphocytes and age will be evaluated for correlation with PFS and OS. | Up to 12 months after study treatment completion | 
| Correlation of clinical response to PFS and OS | Steroid use at the time of leukapheresis and age will be evaluated for correlation with PFS and OS. | Up to 12 months after study treatment completion | 
| Correlation of immune response to PFS and OS | Immune response characteristics will be evaluated for correlation with PFS and OS. | Up to 12 months after study treatment completion | 
| Adverse events, including dose limiting toxicities | Safety of 8 weekly doses of BATs in unmethylated MGMT patients without adjuvant temozolomide | Through 30 days following last dose of EGFR BATs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adoptive Cell Therapy, Armed Activated T-cells, Bispecific Antibodies, Immunotherapy