Clinical trial NCT03344250: Phase I EGFR BATs in Newly Diagnosed Glioblastoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioblastoma
Glioblastoma Multiforme
Keywords: Adoptive Cell Therapy
Armed Activated T-cells
Bispecific Antibodies
Immunotherapy
Lead sponsor: University of Virginia
Sponsor class: OTHER
First posted: 2017-11-17
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: EGFR BATs administered in combination with standard of care temozolomide and radiation
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Histologically-confirmed newly diagnosed intracranial GBM or gliosarcoma
2. Age ≥ 18 years.
3. Karnofsky Performance Status ≥ 60.
4. Be willing and able to provide written informed consent for the trial.
5. 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.
6. Females of childbearing potential, and males, must be willing to use an effective method of contraception
7. 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.
8. 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:

1. 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.
2. Patients with evidence of leptomeningeal dissemination or subependymal spread on initial MRI.
3. Patients with extracranial metastases.
4. Known hypersensitivity to cetuximab or other EGFR antibody.
5. Alpha 1,3 Galactose IgE ("alpha gal") test result outside of the reference range (indicating likely hypersensitivity to cetuximab)
6. Evidence of active bleeding or bleeding diathesis.
7. 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).
8. 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).
9. Has received a live vaccine within 30 days of planned start of study therapy.
10. Has received any treatment for GBM besides surgery.
11. Females must not be breastfeeding.
12. 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.
13. A patient may be excluded if, in the opinion of the treating clinician, the patient is not capable of being compliant.

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: 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 outcomes:
measure: Immune measures in blood- cellular phenotype
timeFrame: 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
measure: Immune measures in blood- interferon-γ
timeFrame: 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
measure: Immune measures in blood- EliSpots
timeFrame: 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
measure: Immune measures in blood- anti-GBM cytotoxicity of peripheral blood mononuclear cells directed at GBM cell lines
timeFrame: 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
measure: Immune measures in blood- serum cytokine patterns
timeFrame: 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
measure: Immune measures in blood- anti-GBM antibodies
timeFrame: 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
measure: Clinical response
timeFrame: Every 3 months following last study visit until death or study closure, expected within 5 years
measure: Survival
timeFrame: Every 3 months following last study visit until death or study closure, expected within 5 years
measure: Response Rate
timeFrame: Every 3 months following last study visit until death or study closure, expected within 5 years
measure: Correlation of imaging to PFS and OS
timeFrame: Up to 12 months after study treatment completion
measure: Correlation of pathology to PFS and OS
timeFrame: Up to 12 months after study treatment completion
measure: Correlation of clinical response to PFS and OS
timeFrame: Up to 12 months after study treatment completion
measure: Correlation of immune response to PFS and OS
timeFrame: Up to 12 months after study treatment completion
measure: Adverse events, including dose limiting toxicities
timeFrame: Through 30 days following last dose of EGFR BATs
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: Samantha Brooks
state: Virginia
Study officials:
affiliation: University of Virginia
name: Camilo Fadul, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lum LG, Thakur A, Al-Kadhimi Z, Colvin GA, Cummings FJ, Legare RD, Dizon DS, Kouttab N, Maizel A, Colaiace W, Liu Q, Rathore R. Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clin Cancer Res. 2015 May 15;21(10):2305-14. doi: 10.1158/1078-0432.CCR-14-2280. Epub 2015 Feb 16.
citation: Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG. Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer. 2015;2015:285193. doi: 10.1155/2015/285193. Epub 2015 Feb 23.