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PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03044743
Recruitment Status : Recruiting
First Posted : February 7, 2017
Last Update Posted : May 2, 2017
Information provided by (Responsible Party):
Yang Yang, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Brief Summary:
This study will evaluate the safety of PD-1 knockout EBV-CTL cells in treating EBV (Epstein-Barr virus) positive advanced stage malignancies. Blood samples will also be collected for research purposes.

Condition or disease Intervention/treatment Phase
Stage IV Gastric Carcinoma Stage IV Nasopharyngeal Carcinoma T-Cell Lymphoma Stage IV Stage IV Adult Hodgkin Lymphoma Stage IV Diffuse Large B-Cell Lymphoma Drug: Fludarabine Drug: Cyclophosphamide Drug: Interleukin-2 Phase 1 Phase 2

Detailed Description:
This is a study of CRISPR-Cas9 mediated PD-1 knockout-T cells from autologous origin. Patients are assigned to receive 4 circles of cell therapy. The safety and clinical response are evaluated. Biomarkers and immunological markers are also monitored.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of PD-1 Knockout EBV-CTLs for Advanced Stage EBV Associated Malignancies
Actual Study Start Date : April 7, 2017
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2022

Arm Intervention/treatment
Experimental: PD-1 knockout EBV-CTL

Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISP-Cas9 system and EBV-CTL will be generated in the laboratory (PD-1 Knockout EBV-CTL).

Fludarabine at 30mg/m2 and Cyclophosphamide at 300mg/m2 single dose will be administered 3 days i.v. before cell infusion.

A total of 2 x 10^7/kg PD-1 Knockout CTL will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third.

Interleukin-2 (IL-2) will be given daily( iv) since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit(IU)/day . Patients will receive a total of four cycles of treatment.

Drug: Fludarabine
To modify immune micro-environment
Other Name: Fludara

Drug: Cyclophosphamide
To modify immune micro-environment
Other Name: Cytoxan

Drug: Interleukin-2
To sustain the survival of infused T cells
Other Name: IL-2

Primary Outcome Measures :
  1. Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients [ Time Frame: 6 months ]

Secondary Outcome Measures :
  1. Response Rate [ Time Frame: 90 days ]
  2. Progression free survival (PFS) [ Time Frame: up to 1 year ]
  3. Overall Survival (OS) [ Time Frame: up to 3 years ]
  4. The duration of the normalization of tumor marker [ Time Frame: up to 3 years ]
  5. Interferon-γ change of T cells in the peripheral blood stimulated by tumor antigens [ Time Frame: Baseline and 1 month, 3 months and 6 months ]
  6. Th1/Th2 change in the peripheral blood [ Time Frame: Baseline and 1 month, 3 months and 6 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Pathologically verified stage IV gastric carcinoma, nasopharyngeal carcinoma and lymphoma with measurable lesions (At least one measurable lesion or the immunotherapy)
  • Pathologically verified as EBV positive malignancies
  • Human leukocyte antigen (HLA) genotypes: HLA-A02, HLA-A24 or HLA-A11 genotypes
  • Progressed after standard treatment or the patients refused to accept the standard treatment
  • Performance score: 0-1
  • Expected life span: >= 3 months
  • Toxicities from prior treatment has resolved. Washout period is 1 months
  • Major organs function normally
  • Women at pregnant ages should be under contraception
  • Willing and able to provide informed consent

Exclusion Criteria:

  • Patients with possible drug allergy of immunotherapy
  • Patients with active bacterial or fungal infections
  • Coagulopathy, or ongoing thrombolytics and/or anticoagulation
  • Blood-borne infectious disease, e.g. hepatitis B, hepatitis C and HIV
  • History of coronary artery disease, asthma, or vascular disease or other disease inappropriate for treatment deemed by treating physician
  • With other tumors except for in situ cervical cancer, treated squamous cell carcinoma and bladder cancer (Ta and TIS) or other malignancies that have been treated with radical therapy (at least for 5 years before the enrollment)
  • With other immune diseases, or chronic use of immunosuppressants or steroids
  • Pregnant and lactating women
  • Compliance cannot be expected
  • Other conditions requiring exclusion deemed by physician

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 identifier (NCT number): NCT03044743

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Contact: Baorui Liu, MD 0086-25-83106666-61331
Contact: Shu Su, MD 0086-25-83106666-61331

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China, Jiangsu
The Comprehensive Cancer Center of Nanjing Drum Tower Hospital Recruiting
Nanjing, Jiangsu, China, 210008
Contact: Yang Yang, MD,PhD,MSCR    0086-18602568379   
Contact: Jing Yan, MD    0086-15805182426   
The Comprehensive Cancer Center of Nanjing Drum Tower Hospital Recruiting
Nanjing, Jiangsu, China, 210008
Contact: Yang Yang    18602568379   
Sponsors and Collaborators
Yang Yang
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Principal Investigator: Baorui Liu, MD The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University

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Responsible Party: Yang Yang, MD, PhD, MSCR, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School Identifier: NCT03044743    
Other Study ID Numbers: PD-1-KO-EBV-CTL
First Posted: February 7, 2017    Key Record Dates
Last Update Posted: May 2, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yang Yang, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School:
advanced stage malignancies
Additional relevant MeSH terms:
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Hodgkin Disease
Lymphoma, Large B-Cell, Diffuse
Nasopharyngeal Carcinoma
Stomach Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Glandular and Epithelial
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Nasopharyngeal Neoplasms
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases