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PD-1 Knockout Engineered T Cells for Metastatic Non-small Cell Lung Cancer

This study is currently recruiting participants.
See Contacts and Locations
Verified November 2016 by You Lu, Sichuan University
Sponsor:
Collaborator:
Chengdu MedGenCell, Co., Ltd.
Information provided by (Responsible Party):
You Lu, Sichuan University
ClinicalTrials.gov Identifier:
NCT02793856
First received: May 30, 2016
Last updated: November 21, 2016
Last verified: November 2016
  Purpose
This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic non-small cell lung cancer. Blood samples will also be collected for research purposes.

Condition Intervention Phase
Metastatic Non-small Cell Lung Cancer Drug: Cyclophosphamide Other: PD-1 Knockout T Cells Drug: Interleukin-2 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Dose-escalation Phase I Trial of PD-1 Knockout Engineered T Cells for the Treatment of Metastatic Non-small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by You Lu, Sichuan University:

Primary Outcome Measures:
  • 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 v4.0) in patients [ Time Frame: Dose Escalation - Approximately 6 months ]

Secondary Outcome Measures:
  • Response Rate [ Time Frame: 90 days ]
    Response will be evaluated according to RECIST v1.1

  • Progression free survival - PFS [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to average 10 months ]
  • Overall Survival - OS [ Time Frame: The time from randomization to death from any cause, assessed up to 2 years ]
  • 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 ]
  • Temporal Interferon-γ change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
  • Temporal tumour necrosis factor-α change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
  • Temporal Interleukin-6 change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]

Estimated Enrollment: 15
Study Start Date: August 2016
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A - Two cycles

Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) 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 infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion.

A total of 2 x 10^7/kg PD-1 Knockout T cells 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 in the following 5 days, 720000 international unit(IU)/Kg/day (if tolerant). Patients will receive a total of two cycles of treatment.

Drug: Cyclophosphamide
To deplete Tregs before collecting peripheral blood
Other Name: Cytoxan
Other: PD-1 Knockout T Cells
Autologous lymphocytes are collected and PDCD1 gene is knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment
Drug: Interleukin-2
Given in the following 5 days at 720,000 international unit(IU)/Kg/day
Other Name: IL-2
Experimental: B- Three cycles

Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) 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 infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion.

A total of 2 x 10^7/kg PD-1 Knockout T cells 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 in the following 5 days, 720000 international unit(IU)/Kg/day (if tolerant). Patients will receive a total of three cycles of treatment.

Drug: Cyclophosphamide
To deplete Tregs before collecting peripheral blood
Other Name: Cytoxan
Other: PD-1 Knockout T Cells
Autologous lymphocytes are collected and PDCD1 gene is knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment
Drug: Interleukin-2
Given in the following 5 days at 720,000 international unit(IU)/Kg/day
Other Name: IL-2
Experimental: C- Four cycles

Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) 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 infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion.

A total of 2 x 10^7/kg PD-1 Knockout T cells 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 in the following 5 days, 720000 international unit(IU)/Kg/day (if tolerant). Patients will receive a total of four cycles of treatment.

Drug: Cyclophosphamide
To deplete Tregs before collecting peripheral blood
Other Name: Cytoxan
Other: PD-1 Knockout T Cells
Autologous lymphocytes are collected and PDCD1 gene is knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment
Drug: Interleukin-2
Given in the following 5 days at 720,000 international unit(IU)/Kg/day
Other Name: IL-2

Detailed Description:
This is a dose-escalation study of ex-vivo knocked-out, expanded, and selected PD-1 knockout-T cells from autologous origin. Patients are assigned to 1 of 3 treatment groups to determine the maximal tolerant dose. After the lower number of cycles are considered tolerant, an arm of the next higher number of cycles will be open to next patients. Biomarkers and immunological markers are collected and analyzed as well.
  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically verified stage IV non-small cell lung cancer with measurable lesions (On CT: longest diameter of tumoral lesion >=10 mm, shorted diameter of lymph node >=15 mm; measurable lesions should not have been irradiated)
  • Progressed after all standard treatment
  • Performance score: 0-1
  • Expected life span: >= 6 months
  • Toxicities from prior treatment has resolved. Washout period is 4 weeks for chemotherapy, and 2 weeks for targeted therapy
  • Major organs function normally
  • Women at pregnant ages should be under contraception
  • Willing and able to provide informed consent

Exclusion Criteria:

  • Pathology is mixed type
  • Emergent treatment of tumor emergency is needed
  • Poor vasculature
  • Coagulopathy, or ongoing thrombolytics and/or anticoagulation
  • 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
  • Compliance cannot be expected
  • Other conditions requiring exclusion deemed by physician
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02793856

Contacts
Contact: You Lu, MD 0086-28-85423571 radyoulu@hotmail.com
Contact: Xiaojuan Zhou, MD 0086-28-85423571 zhouxiaojuan765@163.com

Locations
China, Sichuan
West China Hospital, Sichuan University Recruiting
Chengdu, Sichuan, China, 610041
Contact: You Lu, MD    00862885423571    radyoulu@hotmail.com   
Contact: Xiaojuan Zhou    00862885423571    zhouxiaojuan765@163.com   
Sub-Investigator: Lei Deng, MD         
Sponsors and Collaborators
Sichuan University
Chengdu MedGenCell, Co., Ltd.
Investigators
Principal Investigator: You Lu, MD Sichuan University
  More Information

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: You Lu, Chair of Department of Thoracic Cancer, Sichuan University
ClinicalTrials.gov Identifier: NCT02793856     History of Changes
Other Study ID Numbers: MHC001
Study First Received: May 30, 2016
Last Updated: November 21, 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by You Lu, Sichuan University:
lung cancer
immune checkpoint
PD-1
CRISPER
autologous cell infusion

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Cyclophosphamide
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on September 19, 2017