PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer

• ClinicalTrials.gov Identifier: NCT03081715
• Recruitment Status: Completed
• First Posted: March 16, 2017
• Last Update Posted: June 12, 2019
• Sponsor: Hangzhou Cancer Hospital
• Collaborator: Anhui Kedgene Biotechnology Co.,Ltd
• Information provided by (Responsible Party): Shixiu Wu, Hangzhou Cancer Hospital

Tracking Information

• First Submitted Date: March 11, 2017
• First Posted Date: March 16, 2017
• Last Update Posted Date: June 12, 2019
• Actual Study Start Date: March 14, 2017
• Actual Primary Completion Date: January 23, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 10, 2019)

Response Rate [ Time Frame: 1-3 months ]

Response will be evaluated according to RECIST v1.1

Original Primary Outcome Measures (submitted: March 11, 2017)

Incidence of Treatment-Emergent Adverse Events [ Time Frame: 6 months ]

Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and tolerability of dose of PD-1 Knockout T cells using Common Terminology Criteria for Adverse Events (CTCAE v3.0) in patients

Current Secondary Outcome Measures (submitted: June 10, 2019)

Incidence of Treatment-Emergent Adverse Events [ Time Frame: 6 months ]

Number of participants with Adverse Events and grade as a measure of safety and tolerability of PD-1 knockout T cells using CTCAE v4.03

Original Secondary Outcome Measures (submitted: March 11, 2017)

Response Rate [ Time Frame: 3 months ]

Response will be evaluated according to RECIST v1.1

Current Other Pre-specified Outcome Measures (submitted: June 10, 2019)

• Progression free survival (PFS) [ Time Frame: 1 year ]
  From date of randomization until the date of first documented progression or date of death from any cause
• Overall Survival (OS) [ Time Frame: 1 year ]
  The time from randomization to death from any cause
• Peripheral blood T lymphocyte subsets [ Time Frame: 6 weeks ]
  Sera were collected at baseline and after the first cycle to measure T lymphocyte subsets with flow cytometry
• Tumor-infiltrating T cells [ Time Frame: Baseline and after treatment ]
  Baseline and post-treatment tissue samples were tested for the tumor-infiltrating T cells with immunofluorescence.

Original Other Pre-specified Outcome Measures (submitted: March 11, 2017)

• Progression free survival (PFS) [ Time Frame: 1 year ]
  From date of randomization until the date of first documented progression or date of death from any cause
• Overall Survival (OS) [ Time Frame: 1 year ]
  The time from randomization to death from any cause
• Peripheral blood circulating tumor DNA [ Time Frame: 6 weeks ]
  Peripheral circuiting tumor DNA is collected at baseline and 6 weeks after last treatment
• Temporal Interleukin-2 change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
  Baseline and 1 month and 3 months Interleukin-2 level in blood
• Temporal Interferon-γ change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
  Baseline and 1 month and 3 months Interferon-γ level in blood
• Temporal tumour necrosis factor-α change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
  Baseline and 1 month and 3 months tumour necrosis factor-α level in blood
• Temporal Interleukin-6 change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
  Baseline and 1 month and 3 months Interleukin-6 level in blood

Descriptive Information

• Brief Title: PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer
• Official Title: Safety and Activity of Programmed Cell Death-1 Knockout Engineered T Cells in Patients With Previously Treated Advanced Esophageal Squamous Cell Carcinoma: An Open-label, Single-arm Phase 1 Study
• Brief Summary: This study will evaluate the safety of PD-1 knockout engineered T cells in treating advanced esophageal cancer. Blood or tissue samples will also be collected for research purposes.
• Detailed Description: This is a prospective clinical study of ex-vivo selected, engineered, and expanded PD-1 knockout T cells from autologous origin. 16 advanced esophageal cancer patients are planned to receive two cycles of PD-1 knockout engineered T cells infusion. Immunological markers are analyzed as well.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:

open-label

Primary Purpose: Treatment

• Condition: Esophageal Cancer

Intervention

Other: PD-1 Knockout T Cells

Programmed cell death 1(PD-1) gene will be knocked out by CRISPR Cas9

Study Arms

Experimental: Experimental Group

Peripheral blood lymphocytes will be collected and Programmed cell death 1(PD-1) gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and reinfused back into patients. To avoid allergic reactions, 50 mg hydrocortisone was intravenously injected into the patient 30 min before cells infusion every time. Best supportive care was also provided for patients.

A total of 1 to 10 x 10^9 PD-1 Knockout T cells will be infused each cycle. Patients continued receiving treatment unless they had unacceptable adverse effects, or progressive disease confirmed by CT or they withdrew consent.

Intervention: Other: PD-1 Knockout T Cells

Publications *

• Niu Y, Shen B, Cui Y, Chen Y, Wang J, Wang L, Kang Y, Zhao X, Si W, Li W, Xiang AP, Zhou J, Guo X, Bi Y, Si C, Hu B, Dong G, Wang H, Zhou Z, Li T, Tan T, Pu X, Wang F, Ji S, Zhou Q, Huang X, Ji W, Sha J. Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell. 2014 Feb 13;156(4):836-43. doi: 10.1016/j.cell.2014.01.027. Epub 2014 Jan 30.
• Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967.
• Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015 Apr 9;161(2):205-14. doi: 10.1016/j.cell.2015.03.030.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 10, 2019): 16
• Original Estimated Enrollment (submitted: March 11, 2017): 21
• Actual Study Completion Date: February 28, 2018
• Actual Primary Completion Date: January 23, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed recurrent or metastatic esophageal cancer
• Measurable disease
• Progressed after standard treatments
• ECOG performance status of 0-2
• Expected life span: >= 3 months
• Toxicities from prior treatment has resolved or ≤ grade 1
• Major organs function normally
• Women at pregnant ages should be under contraception
• Willing and able to provide informed consent

Exclusion Criteria:

• Other malignancy within 5 years prior to entry into the study, expect for treated non-melanoma skin cancer and cervical carcinoma in situ
• Poor vasculature
• Disease to the central nervous system
• Blood-borne infectious disease, e.g. hepatitis B
• History of mandatory custody because of psychosis or other psychological disease inappropriate for treatment deemed by treating physician
• With other immune diseases, or chronic use of immunosuppressants or steroids
• Pregnancy (women of childbearing potential:Refusal or inability to use effective means of contraception)
• Breastfeeding
• Decision of unsuitableness by principal investigator or physician-in-charge

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 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: NCT03081715
• Other Study ID Numbers: HangzhouCH07
• Has Data Monitoring Committee: Not Provided

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: Shixiu Wu, Hangzhou Cancer Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Hangzhou Cancer Hospital
• Original Study Sponsor: Same as current
• Collaborators: Anhui Kedgene Biotechnology Co.,Ltd

Investigators

• Principal Investigator: shixiu wu, Professor; Hangzhou Cancer Hospital

• PRS Account: Hangzhou Cancer Hospital
• Verification Date: June 2019