PD-1 Knockout Engineered T Cells for Muscle-invasive Bladder Cancer

Study Overview
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Brief Summary
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This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic advanced bladder cancer. Blood samples will also be collected for research purposes.

Detailed Description
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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.

Official Title
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A Dose-escalation Phase I Trial of PD-1 Knockout Engineered T Cells for the Treatment of Muscle-invasive Bladder Cancer

Conditions
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Invasive Bladder Cancer Stage IV

Intervention / Treatment
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* Biological: PD-1 Knockout T Cells
* Drug: Cyclophosphamide
* Drug: IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically verified stage IV muscle-invasive bladder 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test group<br>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 2, 3, 4 cycles of treatment. | Biological: PD-1 Knockout T Cells<br>* PD-1 Knockout T Cells and PD-1 wild-type T Cells will be made by Cell Biotech Co., Ltd. 2x107/kg T cells will be used for test group and comparable group separately.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/day (if tolerant).<br>* Other names: cytophosphane;Drug: IL-2<br>* Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/day (if tolerant).<br>* Other names: Interleukin-2 (IL-2);|
| Placebo Comparator: Comparable group<br>Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will not be knocked out by CRISPR Cas9 in the laboratory (PD-1 Wild-type 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). | Drug: Cyclophosphamide<br>* Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. Interleukin-2 (IL-2) will be given in the following 5 days, 720000 international unit（IU）/Kg/day (if tolerant).<br>* Other names: cytophosphane;Drug: IL-2<br>* Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/day (if tolerant).<br>* Other names: Interleukin-2 (IL-2);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate:Response will be evaluated according to RECIST v1.1 |  | 90 days | 
| Progression free survival - PFS |  | 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 |  | The time from randomization to death from any cause, assessed up to 2 years | 
| Peripheral blood circulating tumor DNA | Peripheral circuiting tumor DNA is collected at baseline and 6 weeks after last treatment | 6 weeks | 
| Temporal Interleukin-2 change in the peripheral blood |  | Baseline and 1 month and 3 months | 
| Temporal Interferon-γ change in the peripheral blood |  | Baseline and 1 month and 3 months | 
| Temporal Interleukin-6 change in the peripheral blood |  | Baseline and 1 month and 3 months |