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

• ClinicalTrials.gov Identifier: NCT03044743
• Recruitment Status: Unknown
• First Posted: February 7, 2017
• Last Update Posted: May 2, 2017
• Sponsor: Yang Yang
• Information provided by (Responsible Party): Yang Yang, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Tracking Information

• First Submitted Date: January 22, 2017
• First Posted Date: February 7, 2017
• Last Update Posted Date: May 2, 2017
• Actual Study Start Date: April 7, 2017
• Estimated Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 6, 2017): Number of participants with Adverse Events using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients [ Time Frame: 6 months ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 6, 2017)

• Response Rate [ Time Frame: 90 days ]
• Progression free survival (PFS) [ Time Frame: up to 1 year ]
• Overall Survival (OS) [ Time Frame: up to 3 years ]
• The duration of the normalization of tumor marker [ Time Frame: up to 3 years ]
• 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 ]
• Th1/Th2 change in the peripheral blood [ Time Frame: Baseline and 1 month, 3 months and 6 months ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Intervention

• 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

Study Arms

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.

Interventions:

• Drug: Fludarabine
• Drug: Cyclophosphamide
• Drug: Interleukin-2

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: February 6, 2017): 20
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2022
• Estimated Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT03044743
• Other Study ID Numbers: PD-1-KO-EBV-CTL
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Yang Yang, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Original Responsible Party: Same as current
• Current Study Sponsor: Yang Yang
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• 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

• PRS Account: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Verification Date: April 2017