Phase I EGFR BATs in Newly Diagnosed Glioblastoma

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma; Glioblastoma Multiforme
• Intervention / Treatment: Drug: EGFR BATs with TMZ following SOC RT/TMZ; Drug: Weekly EGFR BATs following SOC RT/TMZ

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.

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Samantha Brooks

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Main Study; 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; 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.
Experimental: Subcohort for MGMT unmethylated patients; 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; Standard of care: 6 weeks of RT and TMZ Experimental: 8 weekly doses of EGFR BATs following SOC RT and TMZ

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Virginia
• Investigators: Principal Investigator: Camilo Fadul, MD, University of Virginia

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): December 8, 2021
• Study Completion (Anticipated): December 8, 2024

Study Registration Dates

• First Submitted: November 2, 2017
• First Submitted That Met QC Criteria: November 11, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Estimate): January 25, 2023
• Last Update Submitted That Met QC Criteria: January 23, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Immunotherapy; Adoptive Cell Therapy; Armed Activated T-cells; Bispecific Antibodies
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: 20105 (Other Grant/Funding Number: Arthritis Research UK)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No