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Phase I EGFR BATs in Newly Diagnosed Glioblastoma

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ClinicalTrials.gov Identifier: NCT03344250
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : April 10, 2018
Sponsor:
Information provided by (Responsible Party):
Camilo E. Fadul, MD, University of Virginia

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 and will require a minimum of 3 and a maximum of 18 patients to identify this dose.

Condition or disease Intervention/treatment Phase
Glioblastoma Glioblastoma Multiforme Drug: EGFR BATs with SOC RT and TMZ Phase 1

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
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Intervention Model Description: EGFR BATs administered in combination with standard of care temozolomide and radiation
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 1, 2018
Estimated Primary Completion Date : June 1, 2019
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: EGFR BATs with SOC RT and TMZ
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 SOC RT and TMZ

Standard of care portion of study:

6 weeks of RT and TMZ 6 cycles of TMZ (150-200 mg/m2) on days 1-5 of each 28 day cycle EGFR BATs 2 and 3 weeks after completing RT, and then on day 21 of each cycle of TMZ.





Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: 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 ]
    Maximum tolerated dose will be based on number of dose limiting toxicities at each dose level


Secondary Outcome Measures :
  1. Immune measures in blood- cellular phenotype [ Time Frame: Before surgery (when possible), during screening, at leukapheresis, at 1st and second infusion (2 and 3 weeks after completing RT), and on day 1 of cycles 1, 3, and 5, and 1, 3, 6, and 12 months after completion of EGFR BATs infusions ]
    Sequential monitoring of cellular phenotype

  2. Immune measures in blood- interferon-γ [ Time Frame: Before surgery (when possible), during screening, at leukapheresis, at 1st and second infusion (2 and 3 weeks after completing RT), and on day 1 of cycles 1, 3, and 5, and 1, 3, 6, and 12 months after completion of EGFR BATs infusions ]
    Sequential monitoring of interferon-γ

  3. Immune measures in blood- EliSpots [ Time Frame: Before surgery (when possible), during screening, at leukapheresis, at 1st and second infusion (2 and 3 weeks after completing RT), and on day 1 of cycles 1, 3, and 5, and 1, 3, 6, and 12 months after completion of EGFR BATs infusions ]
    Sequential monitoring of EliSpots

  4. Immune measures in blood- anti-GBM cytotoxicity of peripheral blood mononuclear cells directed at GBM cell lines [ Time Frame: Before surgery (when possible), during screening, at leukapheresis, at 1st and second infusion (2 and 3 weeks after completing RT), and on day 1 of cycles 1, 3, and 5, and 1, 3, 6, and 12 months after completion of EGFR BATs infusions ]
    Sequential monitoring of anti-GBM cytotoxicity of peripheral blood mononuclear cells directed at GBM cell lines

  5. Immune measures in blood- serum cytokine patterns [ Time Frame: Before surgery (when possible), during screening, at leukapheresis, at 1st and second infusion (2 and 3 weeks after completing RT), and on day 1 of cycles 1, 3, and 5, and 1, 3, 6, and 12 months after completion of EGFR BATs infusions ]
    Sequential monitoring of serum cytokine patterns

  6. Immune measures in blood- anti-GBM antibodies [ Time Frame: Before surgery (when possible), during screening, at leukapheresis, at 1st and second infusion (2 and 3 weeks after completing RT), and on day 1 of cycles 1, 3, and 5, and 1, 3, 6, and 12 months after completion of EGFR BATs infusions ]
    Sequential monitoring of anti-GBM antibodies

  7. Clinical response [ Time Frame: Every 3 months following last study visit until death or study closure, expected within 5 years ]
    Progression-free survival (PFS)

  8. Survival [ Time Frame: Every 3 months following last study visit until death or study closure, expected within 5 years ]
    Overall Survival (OS)

  9. Response Rate [ Time Frame: Every 3 months following last study visit until death or study closure, expected within 5 years ]
    Objective Response Rate

  10. Correlation of imaging to PFS and OS [ Time Frame: Up to 12 months after study treatment completion ]
    Imaging (extent of resection) will be evaluated for correlation with PFS and OS.

  11. Correlation of pathology to PFS and OS [ Time Frame: Up to 12 months after study treatment completion ]
    EGFR expression and tumor-infiltrating lymphocytes and age will be evaluated for correlation with PFS and OS.

  12. Correlation of clinical response to PFS and OS [ Time Frame: Up to 12 months after study treatment completion ]
    Steroid use at the time of leukapheresis and age will be evaluated for correlation with PFS and OS.

  13. Correlation of immune response to PFS and OS [ Time Frame: Up to 12 months after study treatment completion ]
    Immune response characteristics will be evaluated for correlation with PFS and OS.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03344250


Contacts
Contact: Melissa Otoya, MSN-CNL 434-982-3365 mo9w@virginia.edu
Contact: Lawrence Lum, MD, DSc 434-243-1375 lgl4f@virginia.edu

Locations
United States, Virginia
University of Virginia Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Melissa Otoya, RN, MSN-CNL    434-982-3365    mo9w@virginia.edu   
Principal Investigator: Camilo Fadul, MD         
Sponsors and Collaborators
University of Virginia
Investigators
Principal Investigator: Camilo Fadul, MD University of Virginia

Publications:
Responsible Party: Camilo E. Fadul, MD, Professor, University of Virginia
ClinicalTrials.gov Identifier: NCT03344250     History of Changes
Other Study ID Numbers: 20105
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: April 10, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Camilo E. Fadul, MD, University of Virginia:
Adoptive Cell Therapy
Armed Activated T-cells
Bispecific Antibodies
Immunotherapy

Additional relevant MeSH terms:
Glioma
Glioblastoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs