Her2 and TGFBeta Cytotoxic T Cells in Treatment of Her2 Positive Malignancy (HERCREEM)

• ClinicalTrials.gov Identifier: NCT00889954
• Recruitment Status: Completed
• First Posted: April 29, 2009
• Last Update Posted: September 18, 2018
• Sponsor: Baylor College of Medicine
• Collaborators: The Methodist Hospital Research Institute; Center for Cell and Gene Therapy, Baylor College of Medicine
• Information provided by (Responsible Party): Stephen Gottschalk, Baylor College of Medicine

Tracking Information

• First Submitted Date: April 24, 2009
• First Posted Date: April 29, 2009
• Last Update Posted Date: September 18, 2018
• Study Start Date: May 2009
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 15, 2018)

Number of Patients with dose limiting toxicity. [ Time Frame: 6 weeks ]

Determine safety of one IV injection of autologous TGFBeta-resistant cytotoxic T cells (CTL) directed to Epstein Barr virus (EBV) through their native receptor and HER2 through their chimeric antigen receptor (CAR) in patients with advanced HER2- positive cancers.

• Original Primary Outcome Measures (submitted: April 28, 2009): Determine safety of one IV injection of autologous TGFBeta-resistant CTLs directed to Epstein Barr virus (EBV) through their native receptor and HER2 through their chimeric antigen receptor (CAR) in patients with advanced HER2-positive lung cancers. [ Time Frame: 15 years ]

Current Secondary Outcome Measures (submitted: April 9, 2018)

• Area under the growth curves (AUC) over time for T cell frequencies. [ Time Frame: 15 years ]
  To compare the survival and the immune function of the TGFBeta-resistant and non resistant components of the infused CAR-CTL.
• Decrease in tumor after the CTL infusion [ Time Frame: 15 years ]
  To assess the anti-tumor effects of the infused CAR-CTL.

Original Secondary Outcome Measures (submitted: April 28, 2009)

• To compare the survival and the immune function of the TGFBeta-resistant and non resistant components of the infused CAR-CTL. [ Time Frame: 15 years ]
• To assess the anti-tumor effects of the infused CAR-CTL. [ Time Frame: 15 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Her2 and TGFBeta Cytotoxic T Cells in Treatment of Her2 Positive Malignancy
• Official Title: Administration of Her2 Chimeric Receptor and TGFbeta Dominant Negative Receptor (DNR) Expressing EBV Specific Lymphocytes for Subjects With Advanced Her2 Positive Malignancy (HERCREEM)

Brief Summary

Patients have advanced stage cancer. This study is a gene transfer research study using special immune cells.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Investigators hope that both will work better together. Antibodies are proteins that protect the body from diseases caused from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both have shown promise, but have not been strong enough to cure most patients.

T lymphocytes can kill tumor cells but there are normally not enough of them or they are not able to kill all the tumor cells. We have done research in which we have grown "extra" T lymphocytes. We have added genes to those T lymphocytes to help them to recognize tumor cells. Although the results have been promising, we are still doing more research in this area.

Antibodies usually circulate in blood and are secreted by other cells of the immune system in response to the presence of germs or abnormal cells in the body. The antibody used in this study is called anti-HER2 (Human Epidermal Growth Factor Receptor 2). This antibody sticks to HER2-positive cancer cells because of a substance on the outside of these cells called HER2.

Detailed Description

The patient will give blood to grow T cells on either one to two separate occasions. Then, the EBV-specific T cells will be made. These cells will be grown and frozen. To get the HER2 antibody (and the CD28) and the DNR to attach to the surface of the EBV-T cells, the antibody gene and the DNR gene will be inserted into the EBV-T cell. This is done with two viruses called retroviruses that have been made for this study. One will carry the antibody gene into the T cell and the other the DNR gene.

When the patient is enrolled on the study, they will be assigned to a dose of HER2-DNR EBV-T cells. The subject will be given one dose of cells into the vein through an IV line. The injection will take between 1 and 10 minutes. The patient will be followed in the clinic after the injection for 1 to 4 hours. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HER2 Positive Malignancies

Intervention

Biological: TGFBeta resistant HER2/EBV-CTLs

Each patient will receive one injection of the TGFBeta resistant HER2/EBV-specific CTLs. Each pt will be followed for 6 weeks after the CTL infusion for evaluation of dose limiting toxicity (DLT).

Patients may receive up to six additional doses of the T cells at 6 to 12 weeks intervals.

Other Name: HER2-DNR EBV T cells

Study Arms

Experimental: TGFBeta resistant HER2/EBV-CTLs

The following dose levels will be evaluated:

Dose Level 1: 1 x 10^4 cells/m^2

Dose Level 2: 3 x 10^4 cells/m^2

Dose Level 5: 1 x 10^6 cells/m^2

Dose Level 6: 3 x 10^6 cells/m^2

Dose Level 7: 1 x 10^7 cells/m^2

Dose Level 8: 3 x 10^7 cells/m^2

Dose Level 9:1 x 10^8 cells/m^2

Intervention: Biological: TGFBeta resistant HER2/EBV-CTLs

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 3, 2017): 20
• Original Estimated Enrollment (submitted: April 28, 2009): 18
• Actual Study Completion Date: January 21, 2018
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

INCLUSION CRITERIA:

The patient must meet the following eligibility inclusion criteria at the time of PROCUREMENT:

1. Diagnosis of advanced stage* or metastatic HER2-positive cancer (Immunohistochemistry or reverse transcription-polymerase chain reaction (RT-PCR) is used to determine HER2 positivity)

   Definitions of Malignancies and Advanced Stages:

   Breast ≥Stage IIIb Colon cancer ≥Stage IIIb Esophageal cancer ≥Stage IIIb Gastric carcinoma ≥Stage IIIb Head and Neck cancer Stage IV Lung cancer ≥Stage IIIb Pancreatic cancer Stage IV Prostate cancer Stage IV

   *it is expected that the majority of patients who will be accrued on the protocol will have one of the HER2-positive malignancies listed in the table. If the patient's malignancy is not listed we will use ≥ Stage IIIb as the definition of advanced stage disease. If Stage IIIb is not part of the staging system for the individual tumor, Stage IV will be used.

   For World Health Organization grade III and IV brain tumors):patients will be eligible, who have recurrent or progressive disease after front line therapy.

2. Karnofsky/Lansky score of 50 or more
3. EBV seropositive
4. Greater than or equal to 3 years old
5. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.

The patient must meet the following eligibility criteria to be included for TREATMENT:

1. Diagnosis of advanced stage* or metastatic HER2-positive cancer with disease progressed after receiving at least one prior systemic therapy. (Immunohistochemistry or RT-PCR is used to determine HER2 positivity) *for definition refer to Table above.
2. Greater than or equal to 3 years old.
3. EBV-seropositive
4. Recovered from the acute toxic effects of all prior chemotherapy at least a week before entering this study.
5. Normal echocardiogram (Left ventricular ejection fraction (LVEF) has to be with in normal, institutional limits)

5. Life expectancy 6 weeks or more

7. Karnofsky/Lansky score of 50 or more

8. Bilirubin 3x or less, Aspartate aminotransferase (AST) 5x or less, Serum creatinine 2x or less upper limit of normal, Hgb 9.0 g/dl or more, white blood cells greater than 2,000/ul, absolute neutrophil count greater than 1,000/ul, Platelets greater than 100,000/ul

9. Pulse oximetry 90% or more on room air

10. Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. Male partner should use a condom. Acceptable forms of birth control include: * oral contraceptives ("the pill"), * intrauterine devices (IUDs), * contraceptive implants under the skin, or contraceptive injections, * condoms with foam.

11. Available autologous transduced EBV-specific cytotoxic T lymphocytes with 15% or more expression of HER2 CAR determined by flow-cytometry and killing of Her2-positive targets 20% or more in cytotoxicity assay.

12. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Note: Patients must also not receive antineoplastic drugs while on this study since they would kill the infused T cells.

EXCLUSION CRITERIA:

At time of Procurement:

1. Known HIV positivity

At time of Treatment:

1. Severe intercurrent infection
2. Known HIV positivity
3. Pregnant or lactating
4. History of hypersensitivity reactions to murine protein-containing products

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00889954
• Other Study ID Numbers: 24486-HERCREEM; HERCREEM ( Other Identifier: Baylor College of Medicine )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Responsible Party: Stephen Gottschalk, Baylor College of Medicine
• Study Sponsor: Baylor College of Medicine

Collaborators

• The Methodist Hospital Research Institute
• Center for Cell and Gene Therapy, Baylor College of Medicine

Investigators

• Principal Investigator: Stepehen Gottschalk, MD; Baylor College of Medicine - Texas Children's Hospital

• PRS Account: Baylor College of Medicine
• Verification Date: September 2018