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TGF-beta Resistant Cytotoxic T-lymphocytes in Treatment of EBV-positive Nasopharyngeal Carcinoma / RESIST-NPC

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ClinicalTrials.gov Identifier: NCT02065362
Recruitment Status : Active, not recruiting
First Posted : February 19, 2014
Last Update Posted : March 21, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Center for Cell and Gene Therapy, Baylor College of Medicine
The Methodist Hospital System
Texas Children's Hospital
Information provided by (Responsible Party):
Helen Heslop, Baylor College of Medicine

Brief Summary:

Patients have nasopharyngeal carcinoma (NPC). This study is a gene transfer research study using special immune cells.

Most patients with NPC show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of almost all patients with advanced stage NPC, suggesting that it may play a role in causing the disease. The cancer cells infected by EBV are able to hide from the body's immune system and escape destruction. We want to see if special white blood cells, called T cells, that have been trained to recognize and kill special parts of EBV infected cells can survive in patient's blood and affect the tumor.

We already have given EBV-specific cytotoxic T cells to 30 patients with active NPC and have seen anti-tumor activity in 14 of 30 patients. We are now trying to find out if we can improve this treatment.

First, we want to give T cells where more of the cells recognize at least two of the four EBV proteins expressed on NPC cells. We call these cells NPC-specific cytotoxic T cells.

Second, we found that T cells work better if we add a receptor to the T cells called DNR (Dominant Negative Receptor). DNR makes T cells resistant to TGFbeta, a factor secreted by cancer cells that helps them escape being killed by the immune system. In this study we will therefore place the DNR gene into NPC-specific T cells (DNR.NPC-specific T cells).

In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in their body, and potentially kill cancer cells more effectively.

The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials.


Condition or disease Intervention/treatment Phase
EBV-positive Nasopharyngeal Carcinoma Biological: DNR.NPC-specific T cells Biological: DNR.NPC-specific T cells + cyclophosphamide + fludarabine Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Administration Of TGF-beta Resistant Cytotoxic T-Lymphocytes to Patients With EBV-positive Nasopharyngeal Carcinoma (RESIST-NPC)
Study Start Date : February 2015
Actual Primary Completion Date : March 2017
Estimated Study Completion Date : February 2033


Arm Intervention/treatment
Experimental: DNR.NPC-specific T cells or DNR.NPC-specific T cells + c/f Biological: DNR.NPC-specific T cells

Each patient will receive 2 infusions, 14 days apart, according to the following dosing schedule:

Dose Level 1:

Day 0: 2 x 10^7 cells/m^2

Day 14: 2 x 10^7 cells/m^2

The doses are calculated according to the total T cell number.


Biological: DNR.NPC-specific T cells + cyclophosphamide + fludarabine

Patients will receive cyclophosphamide and fludarabine for 3 days before receiving the DNR.NPC-specific T cells.

Each patient will receive infusions according to the following dosing schedule:

Dose Level 2:

Cy/Flu on Days -4 to -2 and then 4 x 10^7 cells/m^2 on Day 0, Day 1 or Day 2

Dose Level 3:

Cy/Flu on Days -4 to -2 and then 1 x 10^8 cells/m^2 on Day 0, Day 1, or Day 2





Primary Outcome Measures :
  1. Number of subjects with a dose limiting toxicity [ Time Frame: 8 weeks ]
    Determine the safety of escalating doses of intravenous infusions of autologous TGFbeta-resistant NPC-specific cytotoxic T-lymphocytes with lymphodepleting chemotherapy for dose levels 2 and 3 in patients with EBV-positive nasopharyngeal carcinoma (NPC).


Secondary Outcome Measures :
  1. Amount of T cells in the blood after the infusions [ Time Frame: 15 years ]
    Determine the survival and the immune function of TGFbeta-resistant NPC specific T cells.


Other Outcome Measures:
  1. Number of patients with a response to the T cells [ Time Frame: 8 weeks ]
    Assess the anti-viral and anti-tumor effects of TGFbeta-resistant NPC specific T cells.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

  • Nasopharyngeal Carcinoma in first or subsequent relapse or with primary refractory disease
  • EBV positive tumor
  • 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:

  • Nasopharyngeal Carcinoma in first or subsequent relapse or with primary refractory disease
  • EBV positive tumor
  • Patients with life expectancy greater than or equal to 6 weeks
  • Bilirubin less than or equal to 3x upper limit of normal
  • AST less than or equal to 5x upper limit of normal
  • ANC>750/microliter
  • Platelets > 50,000/microliter
  • Hgb ≥ 7.0g/dl (can be transfused)
  • Creatinine less than or equal to 2x upper limit of normal for age, Creatinine clearance (as estimated by Cockcroft Gault or Schwartz) greater than or equal to 60 ml/min
  • Pulse oximetry of > 90% on room air
  • Off investigational therapy for 4 weeks prior to study entry
  • Karnofsky or Lansky score of greater than or equal to 50%
  • Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom.
  • Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.

Exclusion Criteria:

At time of Procurement:

•Known HIV positivity

At time of Treatment:

  • Pregnant or lactating
  • Severe intercurrent infection

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): NCT02065362


Locations
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United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
National Cancer Institute (NCI)
Center for Cell and Gene Therapy, Baylor College of Medicine
The Methodist Hospital System
Texas Children's Hospital
Investigators
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Principal Investigator: Helen Heslop, MD Baylor College of Medicine/Texas Children's Hospital /Houston Methodist Hospital

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Responsible Party: Helen Heslop, Director CAGT, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT02065362     History of Changes
Other Study ID Numbers: 33954: RESIST-NPC
P01CA094237 ( U.S. NIH Grant/Contract )
First Posted: February 19, 2014    Key Record Dates
Last Update Posted: March 21, 2019
Last Verified: March 2019
Keywords provided by Helen Heslop, Baylor College of Medicine:
EBV positive
TGFbeta
Nasopharyngeal carcinoma
cytotoxic T lymphocytes
Additional relevant MeSH terms:
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Carcinoma
Nasopharyngeal Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Nasopharyngeal Neoplasms
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites