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

Primary Purpose

Invasive Bladder Cancer Stage IV

Status
Withdrawn
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
PD-1 Knockout T Cells
Cyclophosphamide
IL-2
Sponsored by
Peking University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Invasive Bladder Cancer Stage IV

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Urology Peking University First Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Test group

Comparable group

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.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.

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).

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

Response Rate:Response will be evaluated according to RECIST v1.1
Progression free survival - PFS
Overall Survival - OS
Peripheral blood circulating tumor DNA
Peripheral circuiting tumor DNA is collected at baseline and 6 weeks after last treatment
Temporal Interleukin-2 change in the peripheral blood
Temporal Interferon-γ change in the peripheral blood
Temporal Interleukin-6 change in the peripheral blood

Full Information

First Posted
August 1, 2016
Last Updated
March 4, 2019
Sponsor
Peking University
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1. Study Identification

Unique Protocol Identification Number
NCT02863913
Brief Title
PD-1 Knockout Engineered T Cells for Muscle-invasive Bladder Cancer
Official Title
A Dose-escalation Phase I Trial of PD-1 Knockout Engineered T Cells for the Treatment of Muscle-invasive Bladder Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
August 2016
Overall Recruitment Status
Withdrawn
Why Stopped
No funding
Study Start Date
September 2016 (undefined)
Primary Completion Date
September 2019 (Anticipated)
Study Completion Date
September 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Peking University

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 advanced bladder 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
Invasive Bladder Cancer Stage IV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Test group
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.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.
Arm Title
Comparable group
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
PD-1 Knockout T Cells
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
cytophosphane
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
IL-2
Other Intervention Name(s)
Interleukin-2 (IL-2)
Intervention Description
Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/day (if tolerant).
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
Response Rate:Response will be evaluated according to RECIST v1.1
Time Frame
90 days
Title
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
Title
Overall Survival - OS
Time Frame
The time from randomization to death from any cause, assessed up to 2 years
Title
Peripheral blood circulating tumor DNA
Description
Peripheral circuiting tumor DNA is collected at baseline and 6 weeks after last treatment
Time Frame
6 weeks
Title
Temporal Interleukin-2 change in the peripheral blood
Time Frame
Baseline and 1 month and 3 months
Title
Temporal Interferon-γ change in the peripheral blood
Time Frame
Baseline and 1 month and 3 months
Title
Temporal Interleukin-6 change in the peripheral blood
Time Frame
Baseline and 1 month and 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Department of Urology Peking University First Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100034
Country
China

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
plan to share
Citations:
PubMed Identifier
27376121
Citation
Bidnur S, Savdie R, Black PC. Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer. Bladder Cancer. 2016 Jan 7;2(1):15-25. doi: 10.3233/BLC-150026.
Results Reference
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PubMed Identifier
27326412
Citation
Kim J. Immune checkpoint blockade therapy for bladder cancer treatment. Investig Clin Urol. 2016 Jun;57 Suppl 1(Suppl 1):S98-S105. doi: 10.4111/icu.2016.57.S1.S98. Epub 2016 May 26.
Results Reference
background
PubMed Identifier
27306417
Citation
Aragon-Ching JB, Trump DL. Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises. Future Oncol. 2016 Sep;12(17):2049-58. doi: 10.2217/fon-2016-0155. Epub 2016 Jun 16.
Results Reference
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PubMed Identifier
27229745
Citation
Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Melero I, Ascierto PA. Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection? Drugs. 2016 Jun;76(9):925-45. doi: 10.1007/s40265-016-0588-x.
Results Reference
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PubMed Identifier
27402371
Citation
Zibelman M, Plimack ER. Systemic therapy for bladder cancer finally comes into a new age. Future Oncol. 2016 Oct;12(19):2227-42. doi: 10.2217/fon-2016-0135. Epub 2016 Jul 12.
Results Reference
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PubMed Identifier
27460757
Citation
Donin NM, Lenis AT, Holden S, Drakaki A, Pantuck A, Belldegrun A, Chamie K. Immunotherapy for the Treatment of Urothelial Carcinoma. J Urol. 2017 Jan;197(1):14-22. doi: 10.1016/j.juro.2016.02.3005. Epub 2016 Jul 25.
Results Reference
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PubMed Identifier
27641687
Citation
Yi L, Li J. CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges. Biochim Biophys Acta. 2016 Dec;1866(2):197-207. doi: 10.1016/j.bbcan.2016.09.002. Epub 2016 Sep 15.
Results Reference
derived

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

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