PD-1 Knockout Engineered T Cells for Castration Resistant Prostate Cancer

• ClinicalTrials.gov Identifier: NCT02867345
• Recruitment Status: Withdrawn
• First Posted: August 15, 2016
• Last Update Posted: March 6, 2019
• Sponsor: Peking University
• Information provided by (Responsible Party): Wujiang Liu, Peking University

Study Description

Brief Summary:

This study will evaluate the safety of PD-1 knockout engineered T cells in treating castration resistant prostate cancer (CRPC). Blood samples will also be collected for research purposes.

Condition or disease	Intervention/treatment
Hormone Refractory Prostate Cancer	Biological: PD-1 Knockout T Cells; Drug: Cyclophosphamide; Drug: IL-2

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.

Study Design

• Study Type: Observational
• Actual Enrollment: 0 participants
• Observational Model: Other
• Time Perspective: Prospective
• Official Title: A Dose-escalation Phase I Trial of PD-1 Knockout Engineered T Cells for the Treatment of Castration Resistant Prostate Cancer
• Study Start Date: November 2016
• Estimated Primary Completion Date: November 2020
• Estimated Study Completion Date: December 2020

Groups and Cohorts

Group/Cohort	Intervention/treatment
Test group; 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; 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.; Drug: Cyclophosphamide; 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).; Other Name: cytophosphane; Drug: IL-2; Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/ day (if tolerant).; Other Name: Interleukin-2 (IL-2)
Comparable group; 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 wild-type 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; 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).; Other Name: cytophosphane; Drug: IL-2; Interleukin-2 (IL-2) will be given in the following 5 days after cell infusion, 720000 international unit（IU）/Kg/ day (if tolerant).; Other Name: Interleukin-2 (IL-2)

Outcome Measures

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. Response Rate:Response will be evaluated according to RECIST v1.1 [ Time Frame: 90 days ]
2. 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 ]
3. Overall Survival - OS [ Time Frame: The time from randomization to death from any cause, assessed up to 2 years ]
4. Peripheral blood circulating tumor DNA [ Time Frame: 6 weeks ]
5. Temporal Interleukin-2 change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
6. Temporal Interferon-γ change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]
7. Temporal Interleukin-6 change in the peripheral blood [ Time Frame: Baseline and 1 month and 3 months ]

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Pathologically and clinical verified castration resistant prostate 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
• 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

Contacts and Locations

Locations

China, Beijing

Department of Urology Peking University First Hospital

Beijing, Beijing, China, 100034

Sponsors and Collaborators

Peking University

More Information

Publications of Results:

Modena A, Ciccarese C, Iacovelli R, Brunelli M, Montironi R, Fiorentino M, Tortora G, Massari F. Immune Checkpoint Inhibitors and Prostate Cancer: A New Frontier? Oncol Rev. 2016 Apr 15;10(1):293. doi: 10.4081/oncol.2016.293. eCollection 2016 Apr 15.

Bishop JL, Sio A, Angeles A, Roberts ME, Azad AA, Chi KN, Zoubeidi A. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget. 2015 Jan 1;6(1):234-42. doi: 10.18632/oncotarget.2703.

Other Publications:

Taube JM. Unleashing the immune system: PD-1 and PD-Ls in the pre-treatment tumor microenvironment and correlation with response to PD-1/PD-L1 blockade. Oncoimmunology. 2014 Dec 21;3(11):e963413. doi: 10.4161/21624011.2014.963413. eCollection 2014 Nov.

Yatsuda J, Eto M. [Current status and prospects of immunotherapy for castration-resistant prostate cancer]. Nihon Rinsho. 2014 Dec;72(12):2174-8. Japanese.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Wujiang Liu, Professor, Peking University
• ClinicalTrials.gov Identifier: NCT02867345
• Other Study ID Numbers: 11007965939
• First Posted: August 15, 2016
• Last Update Posted: March 6, 2019
• Last Verified: August 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Plan to open

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Cyclophosphamide; Interleukin-2; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents