Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02793856
Recruitment Status : Completed
First Posted : June 8, 2016
Results First Posted : December 21, 2020
Last Update Posted : January 12, 2021
Sponsor:
Collaborator:
Chengdu MedGenCell, Co., Ltd.
Information provided by (Responsible Party):
You Lu, Sichuan University

Brief Summary:
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 or disease Intervention/treatment Phase
Metastatic Non-small Cell Lung Cancer Drug: Cyclophosphamide Other: PD-1 Knockout T Cells Phase 1

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Clinical Trial of PD-1 Knockout Engineered T Cells Treating Patients With Advanced Non-small Cell Lung Cancer
Actual Study Start Date : August 26, 2016
Actual Primary Completion Date : August 20, 2018
Actual Study Completion Date : March 17, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 1 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. 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

Experimental: B- 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. 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

Experimental: C- 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 4 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. 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




Primary Outcome Measures :
  1. 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 :
  1. Number of Patients With Overall Response [ Time Frame: 3 months ]
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR."

  2. Number of Patients With Disease Control at 8 Weeks [ Time Frame: 8 weeks ]
    Response will be evaluated according to RECIST v1.1 for target lesions at Week 8:Complete Response (CR), Disappearance of all extranodal target lesions; Partial Response (PR) ≥ 30% decrease in the sum of diameters of target lesions; Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Disease control = CR +PR+SD

  3. Progression Free Survival (PFS) [ Time Frame: The time from the date of first edited T cell infusion to the date of disease progression or death due to any reason. ]
    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

  4. Overall Survival (OS) [ Time Frame: The duration from date of first edited T cell infusion to the date of death due to any reason ]
    OS is defined as the time interval from date of first edited T cell infusion to the date of death due to any reason

  5. Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) [ Time Frame: Baseline ]
    Driver genes mutaion stauts of Participants in ctDNA from peripheral blood were assessed by next generation sequencing (NGS), to explore the positive rate of sepicif driver genes (e.g. EGFR, ALK, ROS1, etc.) and the relationship between gene mutation status and clinical response

  6. Interleukin-6 Change in the Peripheral Blood. [ Time Frame: Baseline, 1 month and 3 month ]
    Peripheral Interleukin-6 level at different timepoint (Baseline, 1 month and 3 month) was measured using rate nephelometry

  7. Interleukin-10 Change in the Peripheral Blood. [ Time Frame: Baseline, 1 month and 3 month ]
    Peripheral Interleukin-10 level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence.

  8. Tumor Necrosis Factor-a Change in the Peripheral Blood. [ Time Frame: Baseline, 1 month and 3 month ]
    Peripheral Tumor Necrosis Factor-a level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
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

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 ClinicalTrials.gov identifier (NCT number): NCT02793856


Locations
Layout table for location information
China, Sichuan
West China Hospital, Sichuan University
Chengdu, Sichuan, China, 610041
Sponsors and Collaborators
Sichuan University
Chengdu MedGenCell, Co., Ltd.
Investigators
Layout table for investigator information
Principal Investigator: You Lu, MD Sichuan University
  Study Documents (Full-Text)

Documents provided by You Lu, Sichuan University:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: You Lu, Chair of Department of Thoracic Cancer, Sichuan University
ClinicalTrials.gov Identifier: NCT02793856    
Other Study ID Numbers: MHC-001
First Posted: June 8, 2016    Key Record Dates
Results First Posted: December 21, 2020
Last Update Posted: January 12, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by You Lu, Sichuan University:
lung cancer
immune checkpoint
PD-1
CRISPR
autologous cell infusion
Additional relevant MeSH terms:
Layout table for 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
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists