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

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Primary Purpose

Status

Completed

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Cyclophosphamide

PD-1 Knockout T Cells

About this trial

This is an interventional treatment trial for Metastatic Non-small Cell Lung Cancer focused on measuring lung cancer, immune checkpoint, PD-1, CRISPR, autologous cell infusion

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

West China Hospital, Sichuan University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

A - Two cycles

B- Two cycles

C- Two cycles

Arm Description

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.

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.

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.

Outcomes

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

Secondary Outcome Measures

Number of Patients With Overall Response

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."

Number of Patients With Disease Control at 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

Progression Free Survival (PFS)

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

Overall Survival (OS)

OS is defined as the time interval from date of first edited T cell infusion to the date of death due to any reason

Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA)

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

Interleukin-6 Change in the Peripheral Blood.

Peripheral Interleukin-6 level at different timepoint (Baseline, 1 month and 3 month) was measured using rate nephelometry

Interleukin-10 Change in the Peripheral Blood.

Peripheral Interleukin-10 level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence.

Tumor Necrosis Factor-a Change in the Peripheral Blood.

Peripheral Tumor Necrosis Factor-a level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence.

Full Information

NCT ID

NCT02793856

First Posted

May 30, 2016

Last Updated

December 19, 2020

Sponsor

Sichuan University

Collaborators

Chengdu MedGenCell, Co., Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT02793856

Brief Title

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

Official Title

A Phase I Clinical Trial of PD-1 Knockout Engineered T Cells Treating Patients With Advanced Non-small Cell Lung Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

December 2020

Overall Recruitment Status

Completed

Study Start Date

August 26, 2016 (Actual)

Primary Completion Date

August 20, 2018 (Actual)

Study Completion Date

March 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Sichuan University

Collaborators

Chengdu MedGenCell, Co., Ltd.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

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

Metastatic Non-small Cell Lung Cancer

Keywords

lung cancer, immune checkpoint, PD-1, CRISPR, autologous cell infusion

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

A - Two cycles

Arm Type

Experimental

Arm Description

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.

Arm Title

B- Two cycles

Arm Type

Experimental

Arm Description

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.

Arm Title

C- Two cycles

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

To deplete Tregs before collecting peripheral blood

Intervention Type

Other

Intervention Name(s)

PD-1 Knockout T Cells

Intervention Description

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 Measure Information:

Title

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 Measure Information:

Title

Number of Patients With Overall Response

Description

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."

Time Frame

3 months

Title

Number of Patients With Disease Control at 8 Weeks

Description

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

Time Frame

8 weeks

Title

Progression Free Survival (PFS)

Description

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

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.

Title

Overall Survival (OS)

Description

OS is defined as the time interval from date of first edited T cell infusion to the date of death due to any reason

Time Frame

The duration from date of first edited T cell infusion to the date of death due to any reason

Title

Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA)

Description

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

Time Frame

Baseline

Title

Interleukin-6 Change in the Peripheral Blood.

Description

Peripheral Interleukin-6 level at different timepoint (Baseline, 1 month and 3 month) was measured using rate nephelometry

Time Frame

Baseline, 1 month and 3 month

Title

Interleukin-10 Change in the Peripheral Blood.

Description

Peripheral Interleukin-10 level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence.

Time Frame

Baseline, 1 month and 3 month

Title

Tumor Necrosis Factor-a Change in the Peripheral Blood.

Description

Peripheral Tumor Necrosis Factor-a level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence.

Time Frame

Baseline, 1 month and 3 month

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

No

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

You Lu, MD

Organizational Affiliation

Sichuan University

Official's Role

Principal Investigator

Facility Information:

Facility Name

West China Hospital, Sichuan University

City

Chengdu

State/Province

Sichuan

ZIP/Postal Code

610041

Country

China

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Results Reference

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About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial