Metastatic Non-small Cell Lung Cancer
Conditions
Keywords
lung cancer, immune checkpoint, PD-1, CRISPR, autologous cell infusion
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.
Interventions
DRUGCyclophosphamide
To deplete Tregs before collecting peripheral blood
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
Sponsors
Chengdu MedGenCell, Co., Ltd.
Sichuan University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | Dose Escalation - Approximately 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Disease Control at 8 Weeks | 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) | 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 |
| Overall Survival (OS) | 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 |
| Number of Patients With Overall Response | 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. |
| Tumor Necrosis Factor-a Change in the Peripheral Blood. | 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. |
| Interleukin-6 Change in the Peripheral Blood. | Baseline, 1 month and 3 month | 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. | Baseline, 1 month and 3 month | Peripheral Interleukin-10 level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence. |
| Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) | 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 |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pre-A-One Cycle 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 one cycle of treatment.
Cyclophosphamide: To deplete Tregs before collecting peripheral blood
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 | 2 |
| 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.
Cyclophosphamide: To deplete Tregs before collecting peripheral blood
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 | 4 |
| 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.
Cyclophosphamide: To deplete Tregs before collecting peripheral blood
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 | 3 |
| 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.
Cyclophosphamide: To deplete Tregs before collecting peripheral blood
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 | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | B- Two Cycles | C- Two Cycles | A - Two Cycles | Pre-A-One Cycle | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 10 Participants |
| Age, Continuous | 55 years | 53 years | 56 years | 55.5 years | 54.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 4 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 3 participants | 3 participants | 4 participants | 2 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 2 / 2 | 4 / 4 | 3 / 3 | 2 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-A Cohort | 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 | 2 Participants |
| A Cohort | 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 | 4 Participants |
| B Cohort | 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 | 3 Participants |
| C Cohort | 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 | 2 Participants |
Secondary
Interleukin-10 Change in the Peripheral Blood.
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
Population: One patients did not provide blood sample due to early withdrawal; blood samples of 8 patients were only collected at baseline and month 1 due to PD before month 3
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre-A Cohort | Interleukin-10 Change in the Peripheral Blood. | baseline | 5.00 pg/ml |
| Pre-A Cohort | Interleukin-10 Change in the Peripheral Blood. | 1 month | 5.00 pg/ml |
| Pre-A Cohort | Interleukin-10 Change in the Peripheral Blood. | 3 month | 5.00 pg/ml |
| A Cohort | Interleukin-10 Change in the Peripheral Blood. | 1 month | 5.00 pg/ml |
| A Cohort | Interleukin-10 Change in the Peripheral Blood. | baseline | 5.00 pg/ml |
| B Cohort | Interleukin-10 Change in the Peripheral Blood. | 1 month | 19.05 pg/ml |
| B Cohort | Interleukin-10 Change in the Peripheral Blood. | baseline | 5.00 pg/ml |
| B Cohort | Interleukin-10 Change in the Peripheral Blood. | 3 month | 27.10 pg/ml |
| C Cohort | Interleukin-10 Change in the Peripheral Blood. | baseline | 5.00 pg/ml |
| C Cohort | Interleukin-10 Change in the Peripheral Blood. | 1 month | 5.00 pg/ml |
| C Cohort | Interleukin-10 Change in the Peripheral Blood. | 3 month | 5.00 pg/ml |
Secondary
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
Time frame: Baseline, 1 month and 3 month
Population: One patients did not provide blood sample due to early withdrawal; blood samples of 8 patients were only collected at baseline and month 1 due to PD before month 3
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre-A Cohort | Interleukin-6 Change in the Peripheral Blood. | baseline | 10.68 pg/ml |
| Pre-A Cohort | Interleukin-6 Change in the Peripheral Blood. | 1 month | 12.9 pg/ml |
| Pre-A Cohort | Interleukin-6 Change in the Peripheral Blood. | 3 month | 18.45 pg/ml |
| A Cohort | Interleukin-6 Change in the Peripheral Blood. | 1 month | 4.37 pg/ml |
| A Cohort | Interleukin-6 Change in the Peripheral Blood. | baseline | 3.27 pg/ml |
| B Cohort | Interleukin-6 Change in the Peripheral Blood. | 1 month | 23.92 pg/ml |
| B Cohort | Interleukin-6 Change in the Peripheral Blood. | baseline | 51.97 pg/ml |
| B Cohort | Interleukin-6 Change in the Peripheral Blood. | 3 month | 4.03 pg/ml |
| C Cohort | Interleukin-6 Change in the Peripheral Blood. | baseline | 10.59 pg/ml |
| C Cohort | Interleukin-6 Change in the Peripheral Blood. | 1 month | 14.77 pg/ml |
| C Cohort | Interleukin-6 Change in the Peripheral Blood. | 3 month | 12.49 pg/ml |
Secondary
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
Time frame: Baseline
Population: Only three patients were detected with EGFR mutations. Correlation between driver gene mutations with clinical outcome were not analyzed due to limited data. EGFR positive rate was showed in outcome measure data table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-A Cohort | Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) | 0 Participants |
| A Cohort | Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) | 1 Participants |
| B Cohort | Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) | 1 Participants |
| C Cohort | Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) | 1 Participants |
Secondary
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
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-A Cohort | Number of Patients With Disease Control at 8 Weeks | 1 Participants |
| A Cohort | Number of Patients With Disease Control at 8 Weeks | 0 Participants |
| B Cohort | Number of Patients With Disease Control at 8 Weeks | 1 Participants |
| C Cohort | Number of Patients With Disease Control at 8 Weeks | 0 Participants |
Secondary
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.
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-A Cohort | Number of Patients With Overall Response | 0 Participants |
| A Cohort | Number of Patients With Overall Response | 0 Participants |
| B Cohort | Number of Patients With Overall Response | 0 Participants |
| C Cohort | Number of Patients With Overall Response | 0 Participants |
Secondary
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
Time frame: The duration from date of first edited T cell infusion to the date of death due to any reason
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pre-A Cohort | Overall Survival (OS) | 47.5 weeks |
| A Cohort | Overall Survival (OS) | 51.4 weeks |
| B Cohort | Overall Survival (OS) | 32.6 weeks |
| C Cohort | Overall Survival (OS) | 51.6 weeks |
Secondary
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
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pre-A Cohort | Progression Free Survival (PFS) | 11.7 weeks |
| A Cohort | Progression Free Survival (PFS) | 8.0 weeks |
| B Cohort | Progression Free Survival (PFS) | 8.1 weeks |
| C Cohort | Progression Free Survival (PFS) | 6.1 weeks |
Secondary
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.
Time frame: Baseline, 1 month and 3 month
Population: One patients did not provide blood sample due to early withdrawal; blood samples of 8 patients were only collected at baseline and month 1 due to PD before month 3
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre-A Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | baseline | 13.84 pg/ml |
| Pre-A Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 1 month | 10.68 pg/ml |
| Pre-A Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 3 month | 6.97 pg/ml |
| A Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 1 month | 7.84 pg/ml |
| A Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | baseline | 6.07 pg/ml |
| B Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 1 month | 10.40 pg/ml |
| B Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | baseline | 8.89 pg/ml |
| B Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 3 month | 10.90 pg/ml |
| C Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | baseline | 5.06 pg/ml |
| C Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 1 month | 16.4 pg/ml |
| C Cohort | Tumor Necrosis Factor-a Change in the Peripheral Blood. | 3 month | 11.70 pg/ml |