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

Primary Purpose

Stage IV Gastric Carcinoma, Stage IV Nasopharyngeal Carcinoma, T-Cell Lymphoma Stage IV

Status

Unknown status

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Fludarabine

Cyclophosphamide

Interleukin-2

About this trial

This is an interventional treatment trial for Stage IV Gastric Carcinoma focused on measuring PD-1, CRISPR Cas9, EBV, advanced stage malignancies

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

The Comprehensive Cancer Center of Nanjing Drum Tower HospitalRecruiting
The Comprehensive Cancer Center of Nanjing Drum Tower HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PD-1 knockout EBV-CTL

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients

Secondary Outcome Measures

Response Rate

Progression free survival (PFS)

Overall Survival (OS)

The duration of the normalization of tumor marker

Interferon-γ change of T cells in the peripheral blood stimulated by tumor antigens

Th1/Th2 change in the peripheral blood

Full Information

NCT ID

NCT03044743

First Posted

January 22, 2017

Last Updated

April 28, 2017

Sponsor

Yang Yang

1. Study Identification

Unique Protocol Identification Number

NCT03044743

Brief Title

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

Official Title

A Phase I/II Trial of PD-1 Knockout EBV-CTLs for Advanced Stage EBV Associated Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Unknown status

Study Start Date

April 7, 2017 (Actual)

Primary Completion Date

March 2020 (Anticipated)

Study Completion Date

March 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Yang Yang

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

PD-1, CRISPR Cas9, EBV, advanced stage malignancies

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

PD-1 knockout EBV-CTL

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

To modify immune micro-environment

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

To modify immune micro-environment

Intervention Type

Drug

Intervention Name(s)

Interleukin-2

Other Intervention Name(s)

IL-2

Intervention Description

To sustain the survival of infused T cells

Primary Outcome Measure Information:

Title

Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Response Rate

Time Frame

90 days

Title

Progression free survival (PFS)

Time Frame

up to 1 year

Title

Overall Survival (OS)

Time Frame

up to 3 years

Title

The duration of the normalization of tumor marker

Time Frame

up to 3 years

Title

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

Title

Th1/Th2 change in the peripheral blood

Time Frame

Baseline and 1 month, 3 months and 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Baorui Liu, MD

Phone

0086-25-83106666-61331

baoruiliu07@163.com

First Name & Middle Initial & Last Name or Official Title & Degree

Shu Su, MD

Phone

0086-25-83106666-61331

ssnine@126.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Baorui Liu, MD

Organizational Affiliation

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Comprehensive Cancer Center of Nanjing Drum Tower Hospital

City

Nanjing

State/Province

Jiangsu

ZIP/Postal Code

210008

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yang Yang, MD,PhD,MSCR

Phone

0086-18602568379

wing_young7@hotmail.com

First Name & Middle Initial & Last Name & Degree

Jing Yan, MD

Phone

0086-15805182426

firefreebird@163.com

Facility Name

The Comprehensive Cancer Center of Nanjing Drum Tower Hospital

City

Nanjing

State/Province

Jiangsu

ZIP/Postal Code

210008

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yang Yang

Phone

18602568379

wing_young7@hotmail.com

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

25254613

Citation

Kim SY, Park C, Kim HJ, Park J, Hwang J, Kim JI, Choi MG, Kim S, Kim KM, Kang MS. Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes. Gastroenterology. 2015 Jan;148(1):137-147.e9. doi: 10.1053/j.gastro.2014.09.020. Epub 2014 Sep 22.

Results Reference

background

PubMed Identifier

26361042

Citation

Quan L, Chen X, Liu A, Zhang Y, Guo X, Yan S, Liu Y. PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro. PLoS One. 2015 Sep 11;10(9):e0136476. doi: 10.1371/journal.pone.0136476. eCollection 2015.

Results Reference

background

PubMed Identifier

20948438

Citation

Louis CU, Straathof K, Bollard CM, Ennamuri S, Gerken C, Lopez TT, Huls MH, Sheehan A, Wu MF, Liu H, Gee A, Brenner MK, Rooney CM, Heslop HE, Gottschalk S. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother. 2010 Nov-Dec;33(9):983-90. doi: 10.1097/CJI.0b013e3181f3cbf4.

Results Reference

background

PubMed Identifier

23935598

Citation

Lloyd A, Vickery ON, Laugel B. Beyond the antigen receptor: editing the genome of T-cells for cancer adoptive cellular therapies. Front Immunol. 2013 Aug 5;4:221. doi: 10.3389/fimmu.2013.00221. eCollection 2013.

Results Reference

background

PubMed Identifier

26818188

Citation

Su S, Hu B, Shao J, Shen B, Du J, Du Y, Zhou J, Yu L, Zhang L, Chen F, Sha H, Cheng L, Meng F, Zou Z, Huang X, Liu B. CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients. Sci Rep. 2016 Jan 28;6:20070. doi: 10.1038/srep20070. Erratum In: Sci Rep. 2017 Jan 19;7:40272.

Results Reference

background

PubMed Identifier

24076990

Citation

Mali P, Esvelt KM, Church GM. Cas9 as a versatile tool for engineering biology. Nat Methods. 2013 Oct;10(10):957-63. doi: 10.1038/nmeth.2649.

Results Reference

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

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