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A Phase I study of autologous hTERT-specific CD8+ T cell immunotherapy in patients with advanced solid tumors who failed standard therapy

Status Approved

First Submitted Date

2018/11/07
Registered Date

2019/06/13
Last Updated Date

2019/06/13

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CRIS Required

WHO ICTRP (International Clinical Trial Registry Platform) Required

1. Background

Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
CRIS Registration Number	KCT0004064
Unique Protocol ID	NCCCTS13714
Public/Brief Title	Clinical trial of autologous tumor-specific T cells
Scientific Title	A Phase I study of autologous hTERT-specific CD8+ T cell immunotherapy in patients with advanced solid tumors who failed standard therapy
Acronym
MFDS Regulated Study	Yes
IND/IDE Protocol	Yes
Registered at Other Registry	No
Healthcare Benefit Approval Status	Not applicable

2. Institutional Review Board / Ethics Committee

Institutional Review Board Information
Board Approval Status	Submitted approval
Board Approval Number	NCCCTS13714
Approval Date	2014-01-06
Institutional Review Board Name	National Cancer Center Institutional Review Board
Institutional Review Board Address	323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
Institutional Review Board Telephone	031-920-0425
Data Monitoring Committee

3. Contact Details

Contact Details Information - Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Contact Person for Updating Information의 Name, Title, Email, Telephone, Cellular Phone, Affiliation, Address
Contact Person for Principal Investigator / Scientific Queries
Name	Young Joo Lee
Title	MD
Telephone	+82-31-920-1694
Affiliation	National Cancer Center
Address	323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
Contact Person for Public Queries
Name	Young Joo Lee
Title	MD
Telephone	+82-31-920-1694
Affiliation	National Cancer Center
Address	323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do
Contact Person for Updating Information
Name	Young Joo Lee
Title	MD
Telephone	+82-31-920-1694
Affiliation	National Cancer Center
Address	323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do

4. Status

Status Information - Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt
Recruitment Status by Participating Study Site 1
Study Site	Single
Overall Recruitment Status	Recruiting
Date of First Enrollment	2014-04-29 Actual
Target Number of Participant	24
Primary Completion Date	2019-07-30 , Anticipated
Study Completion Date	2019-07-30 , Anticipated
Name of Study	National Cancer Center
Recruitment Status	Recruiting
Date of First Enrollment	2014-04-29 ,

5. Source of Monetary / Material Support

Source of Monetary / Material Support Information - Organization Name, Organization Type, Project ID
1. Source of Monetary/Material Support
Organization Name	Korea Institute for Advancement of Technology
Organization Type	Others
Project ID	N0000901

6. Sponsor Organization

Sponsor Organization Information - Organization Name, Organization Type
1. Sponsor Organization
Organization Name	National Cancer Center
Organization Type	Medical Institute

7. Study Summary

Study Summary Information
Lay Summary	Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, we successfully isolate and expand hTERT-specific CD8 T (TERTiNT) cells from PBMCs of patients with solid cancers. Since hTERT is over-expressed in most of sold cancer cells, hTERT-specific CD8 T cells are expected to be used to treat most of solid cancers This protocol proposes to test the hypothesis that autologous hTERT-specific CD8 T cells are safe and can augment the potency of anti-tumor responses of patient with solid cancers. Therefore, the purpose of this study is: Primary objectives 1. To determine the maximum tolerated dose of TERTiNT cells in in standard therapy-failed recurrent sold cancer patients. 2. To evaluate the safety of autologous TERTiNT cells in standard therapy-failed recurrent sold cancer patients Secondary objectives 3. To investigate the potential antitumor effects of TERTiNT cells in standard therapy-failed recurrent sold cancer patients

Study Summary Information

Lay Summary

Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, we successfully isolate and expand hTERT-specific CD8 T (TERTiNT) cells from PBMCs of patients with solid cancers. Since hTERT is over-expressed in most of sold cancer cells, hTERT-specific CD8 T cells are expected to be used to treat most of solid cancers
	This protocol proposes to test the hypothesis that autologous hTERT-specific CD8 T cells are safe and can augment the potency of anti-tumor responses of patient with solid cancers. Therefore, the purpose of this study is:
Primary objectives
1.	To determine the maximum tolerated dose of TERTiNT cells in in standard therapy-failed recurrent sold cancer patients.
2.	To evaluate the safety of autologous TERTiNT cells in standard therapy-failed recurrent sold cancer patients
Secondary objectives
3.	To investigate the potential antitumor effects of TERTiNT cells in standard therapy-failed recurrent sold cancer patients

8. Study Design

Study Design Information - Study Type, Study Purpose, Phase, Intervention Model, Blinding/Masking, Blinded Subject, Allocation, Intervention Type, Intervention Description, Number of Arms, Arm Label, Target Number of Participant, Arm Type, Arm Description
Study Type	Interventional Study
Study Purpose	Treatment
Phase	Phase1
Intervention Model	Parallel
Blinding/Masking	Open
Allocation	Non-RCT
Intervention Type	/Biological/Vaccine, /Non-Stem Cell
Intervention Description	1. Drug: autologous hTERT-specific cD8 T cells (TERTiNT cells) 2. Dose - Dose 1: 4.0 x 10e8/m2 (day 0) - Dose 2: 1g/m2 cytoxan (day -3) + 4.0 x 10e8/m2 (day 0) - Dose 3: 1g/m2 cytoxan (day -3) + 4.0 x 10e8/m2 (day 0) + 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day) - Dose 4: 1g/m2 cytoxan (day -3) + 8.0 x 10e8/m2 (day 0) + 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day) - Dose 5: 1g/m2 cytoxan (day -5) + 25mg/m2 fludarabine (day -4 & -3) + 8.0 x 10e8/m2 (day 0) + 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day) - Dose 6: 1g/m2 cytoxan (day -5) + 25mg/m2 fludarabine (day -4 & -3) + 16.0 x 10e8/m2 (day 0) + 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day) 3. Treatment plan 1) Peripheral blood mononuclear cells are isolated from 50ml heparinized blood and culture for 31 days to isolate and expand hTERT-specific CD8 T cells. 2) Prior injection of cyclophosphamide +/- fludarabine to the patient via i.v. route according to the dose schedule. 3) Single injection of TERTiNT cells via i.v. route at day 0 according to the dose schedule. 4) Intramuscular injection of 250,000U IU/m2 IL-2 to the patient 6hr after TERTiNT infusion (day 0-7, B.I.D./day, upto 14 times). 5) Evaluate acute adverse reaction 4 weeks after TERTiNT infusion.
Number of Arms	6
Arm 1	Arm Label Dose 1
	Target Number of Participant 3
	Arm Type Experimental
	Arm Description I.v. injection of TERTiNT Cell at day 0 Dose : 4.0 x 10e8/m2
Arm 2	Arm Label Dose 2
	Target Number of Participant 3
	Arm Type Active comparator
	Arm Description - I.v. injection of 1g/m2 cytoxan at day -3 - I.v. injection of TERTiNT Cell at day 0: 4.0 x 10e8/m2 TERTiNT cells
Arm 3	Arm Label Dose 3
	Target Number of Participant 3
	Arm Type Active comparator
	Arm Description - I.v. injection of 1g/m2 cytoxan at day -3 - I.v. injection of TERTiNT Cell at day 0: 4.0 x 10e8/m2 TERTiNT cells - I.m. injection of 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day)
Arm 4	Arm Label Dose 4
	Target Number of Participant 6
	Arm Type Active comparator
	Arm Description - I.v. injection of 1g/m2 cytoxan at day -3 - I.v. injection of TERTiNT Cell at day 0: 8.0 x 10e8/m2 TERTiNT cells - I.m. injection of 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day)
Arm 5	Arm Label Dose 5
	Target Number of Participant 3
	Arm Type Active comparator
	Arm Description - I.v. injection of 1g/m2 cytoxan at day -5 - I.v. injection of 25mg/m2 fludarabine at day -4 & -3 - I.v. injection of TERTiNT Cell at day 0: 8.0 x 10e8/m2 TERTiNT cells - I.m. injection of 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day)
Arm 6	Arm Label Dose 6
	Target Number of Participant 6
	Arm Type Active comparator
	Arm Description - I.v. injection of 1g/m2 cytoxan at day -5 - I.v. injection of 25mg/m2 fludarabine at day -4 & -3 - I.v. injection of TERTiNT Cell at day 0: 16.0 x 10e8/m2 TERTiNT cells - I.m. injection of 250,000 IU/m2 human IL-2 (day 0-7, B.I.D./day)

9. Subject Eligibility

Subject Eligibility Information
Condition(s)/Problem(s)	* (C00-D48)Neoplasms (C80.9)Malignant neoplasm, primary site unspecified advanced solid tumors who failed standard therapy
Rare Disease	No
Inclusion Criteria	Gender Both
	Age 20Year~75Year
	Description 1) Subjects must be 20 ~ 75 years old 2) Patients with standard therapy-failed reccurrent sold cancers 3) Patients with hTERT-specific CD8 T cells in prior epitope screening. 4) Performance Status Score (ECOG/Zubrod Scale) must be =< 2
Exclusion Criteria	1) Patients who have Symptoms- or unregulated with metastasis in CNS 2) Patients recieved all immunosuppressive treatments such as chemotherapy or radiotherapy a minimum of 3 weeks prior to initiation of study 3) Leukocyte number < 2,500/ul, absolute numbers of neutrophils < 1,000/ul, platelet numbers < 50,000/ul, hemoglobin <9g/dL, serum creatinine > 2.0mg/dL, AST/ALT > 3x upper limit of normal range (ULN), total bilirubin > 2.0 mg/dL, Prothrombin time > 1.5 x ULN 4) Active cardiovascular diseases, including: unregulated hypertension( Systolic blood pressure>180mmHg, Diastolic blood pressure>100mmHg), Unstable angina, Pulmonary embolisim, cerebrovascular disease, valvular disease of the heart , congestive heart failure or myocardial infarction in the last 6 months, or severe arrhythmia 5) Anti-HIV Ab positive 6) Patients with active autoimmune diseases or inflammatory diseases 7) Uncontrolled active infection/neurologic diseases 8) Patients with a previous history of immune cell therapy 9) Pregnant or breast-feeding women
Healthy Volunteers	No

10. Outcome Measure(s)

Outcome Measure(s) Information - Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint
Primary Outcome(s) 1
Type of Primary Outcome	/Safety/Efficacy
Outcome	To determine maximum tolerated dose of autologous hTERT-specific CD8 T cells in patients with standard therapy-failed recurrent solid cancers
Timepoint	4 weeks after infusion of TERTiNT cells
Secondary Outcome(s) 1
Outcome	Dose-limiting toxicity
Timepoint	4 weeks after infusion of TERTiNT cells
Secondary Outcome(s) 2
Outcome	safety
Timepoint	4 weeks after infusion of TERTiNT cells
Secondary Outcome(s) 3
Outcome	adverse effects
Timepoint	24 weeks after infusion of TERTiNT cells
Secondary Outcome(s) 4
Outcome	effectiveness
Timepoint	24 weeks after infusion of TERTiNT cells

11. Study Results and Publication

Study Results and Publication Information - Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary
Result Registered	No

12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

Sharing of Study Data Information - Sharing Statement, Time of Sharing, Way of Sharing
Sharing Statement	Yes
Time of Sharing	2020. 6
Way of Sharing	To be made available at a later date (73933@ncc.re.kr)

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