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Safety and Efficacy Evaluation of MUC-1 CART in the Treatment of Intrahepatic Cholangiocarcinoma

Primary Purpose

Intrahepatic Cholangiocarcinoma

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
MUC-1 CART cell immunotherapy
Sponsored by
Second Affiliated Hospital, School of Medicine, Zhejiang University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Intrahepatic Cholangiocarcinoma focused on measuring ICC, Mucin-1, CAR-T, Immunotherapy

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 18-65 years old.
  2. The expression of ST glycosylated MUC-1 was more than 1+ in immunohistochemistry(IHC) by applicant-approved laboratory.
  3. Histopathology or cytology confirmed intrahepatic cholangiocarcinoma.
  4. Patients who are unable to perform surgery or are not suitable for surgery, or who have recurrence after surgery, or who are unwilling to undergo chemotherapy.
  5. With at least one extracranial measurable lesion according to RECIST 1.1 edition.
  6. The expected survival time is more than 60 days.
  7. The main organs are functional and meet the following criteria:

1) ECOG physical fitness score was 0~1 or KPS score >70. 2) Routine blood tests were in accordance with the following criteria: HB (>90 g/L) (no blood transfusion within 14 days), ANC (>1.5 x10^9/L), PLT (> 80 x10^9/L), lymphocyte (> 0.7 x10^9/L), LY (> 15%), Alb (> 2.8 g/dL), serum lipase and amylase < 1.5^ULN (upper limit of normal value).

3) Biochemical examination should meet the following criteria: TBIL < 1.5x ULN (upper limit of normal value); ALT < 2.5 xULN; serum Cr<1 xULN; endogenous creatinine clearance > 50ml/min (Cockcroft-Gault formula).

4) Cardiac ejection fraction >55%. 8. No active hemorrhagic disease or severe coagulation dysfunction. 9. No allergy to the contrast media. 10. Women of childbearing age must undergo a pregnancy test (serum or urine) within 7 days before enrollment, and the results are negative, and are willing to use appropriate contraception methods during the experiment and 8 weeks after the last CART.

11. The volunteers voluntarily joined the study, signed informed consent, and had good compliance and follow-up.

Exclusion Criteria:

  1. The transduction efficiency of T cells was <10% or T cells expanded less than 5 times after culture.
  2. Chimeric antigen receptor therapy or other transgenic T cell therapy.
  3. Pregnant or lactating women.
  4. In the first 4 weeks before the start of the study, they took part in other drug clinical trials.
  5. Patients with hypertension who can not be well controlled by a single antihypertensive drug (SBP> 140 mmHg, DBP> 90 mmHg), myocarditis or congenital heart disease, myocardial ischemia or infarction above grade I, arrhythmia above grade I (including QT interval < 440 ms) or cardiac insufficiency.
  6. Long term unhealed wounds or fractures.
  7. With a history of psychotropic substance abuse and unable to quit or have a history of mental disorders.
  8. Past and current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of lung function, etc.
  9. With uncontrollable fungi, bacteria, viruses or other infections, or need antibacterial treatment. The presence of simple urinary tract infections and uncomplicated bacterial pharyngitis is allowed after consultation with a medical supervisor, if there is a response to active therapy.
  10. According to the NCI-CTCAE 4.0 standard, the patients who had used chemotherapy in the past had grade 2 hematological toxicity or grade 3 non-hematological toxicity.
  11. With a history of HIV or hepatitis B or hepatitis C virus infection.
  12. There are any indwelling catheters or drainage tubes (e.g. percutaneous nephrostomy, Frey's catheter, bile drainage or pleural/peritoneal/pericardial catheter). The use of dedicated central venous catheters is permitted.
  13. With brain metastases.
  14. With a history or disease of CNS, such as epileptic seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving CNS.
  15. With a major immunodeficiency.
  16. The main therapeutic drugs in this study (including fludarabine, cyclophosphamide, sodium mesylate, tropizumab and anti-infective drugs used during pretreatment) had a history of severe hypersensitivity.
  17. In the first 6 months of admission, there was a history of deep venous thrombosis or pulmonary embolism.
  18. History of autoimmune diseases (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) that cause terminal organ injury or require systemic immunosuppressive/systemic disease-regulating drugs.
  19. With any diseases that may interfere with the safety or efficacy of treatment.

Sites / Locations

  • The second affiliated hospital of Zhejiang UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

MUC-1 CART

Arm Description

Patients are given fludarabine and cyclophosphamide as pretreatment before MUC-1 CART immunotherapy. After treatment, specific antibodies, CART cells and serum levels of cytokines will be assessed.

Outcomes

Primary Outcome Measures

Disease control rate
Percentage of patients whose cancer doesn't progress after treatment

Secondary Outcome Measures

Objective response rate
Percentage of patients whose cancer shrinks or disappears after treatment
Duration of overall response
The time of initial response until documented tumor progression.
Progression-free survival
The percentage of people does not get worse for a period of time after diagnosis
Overall survival
The percentage of people still alive for a given period of time after diagnosis
Common Toxicity Criteria for Adverse Effects
According to Common Toxicity Criteria for Adverse Effects version 4
EORTC QLQ - PAN26
Assessed by the European Organization for Research and Treatment of Cancer Quality of Life
Anti-MUC1 CART cell antibody
Serum level of anti-MUC1 CART cell antibody
MUC1 CART cell
Serum level of MUC-1 CART cell
Related cytokine
Serum level of related cytokine(like IL-2、IL-6、TNF-α、IFNγ and so on)

Full Information

First Posted
August 14, 2018
Last Updated
August 20, 2018
Sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University
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1. Study Identification

Unique Protocol Identification Number
NCT03633773
Brief Title
Safety and Efficacy Evaluation of MUC-1 CART in the Treatment of Intrahepatic Cholangiocarcinoma
Official Title
Safety and Efficacy Evaluation of MUC-1 CART in the Treatment of Intrahepatic Cholangiocarcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2018 (Actual)
Primary Completion Date
August 31, 2023 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Intrahepatic cholangiocarcinoma (ICC) is one of the most common liver malignancies. Surgical treatment is the first choice. However, for patients without surgical indications, the benefits of conventional chemoradiotherapy are limited. CART is one of the fastest developed treatments in recent years. MUC-1 CART can target abnormal glycosylation of MUC-1 and then killing tumor specifically. Here, investigators intend to evaluate the safety and efficacy of MUC-1 CART in intrahepatic cholangiocarcinoma.
Detailed Description
Investigators chose MUC-1 positive intrahepatic cholangiocarcinoma patients with one measurable lesion at least. After general assessment, MUC-1 CART treatment was given to the participants. Objective remission rate, disease control rate, duration of overall response, progression-free survival, overall survival, drugs related side effects and other endpoints events were recorded and analyzed, to assess the MUC-1 CART could or couldn't effectively control the progress of intrahepatic cholangiocarcinoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intrahepatic Cholangiocarcinoma
Keywords
ICC, Mucin-1, CAR-T, Immunotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
MUC-1 CART
Arm Type
Experimental
Arm Description
Patients are given fludarabine and cyclophosphamide as pretreatment before MUC-1 CART immunotherapy. After treatment, specific antibodies, CART cells and serum levels of cytokines will be assessed.
Intervention Type
Biological
Intervention Name(s)
MUC-1 CART cell immunotherapy
Intervention Description
After fludarabine and cyclophosphamide pre-chemotherapy,MUC-1 CART immunotherapy is given. A decent interval later, levels of specific antibodies, CART cells and serum cytokines will be assessed.
Primary Outcome Measure Information:
Title
Disease control rate
Description
Percentage of patients whose cancer doesn't progress after treatment
Time Frame
Up to approximately 12 months
Secondary Outcome Measure Information:
Title
Objective response rate
Description
Percentage of patients whose cancer shrinks or disappears after treatment
Time Frame
Up to approximately 12 months
Title
Duration of overall response
Description
The time of initial response until documented tumor progression.
Time Frame
Up to approximately 12 months
Title
Progression-free survival
Description
The percentage of people does not get worse for a period of time after diagnosis
Time Frame
Up to approximately 12 months
Title
Overall survival
Description
The percentage of people still alive for a given period of time after diagnosis
Time Frame
Up to approximately 12 months
Title
Common Toxicity Criteria for Adverse Effects
Description
According to Common Toxicity Criteria for Adverse Effects version 4
Time Frame
Up to approximately 12 months
Title
EORTC QLQ - PAN26
Description
Assessed by the European Organization for Research and Treatment of Cancer Quality of Life
Time Frame
Up to approximately 12 months
Title
Anti-MUC1 CART cell antibody
Description
Serum level of anti-MUC1 CART cell antibody
Time Frame
Up to approximately 12 months
Title
MUC1 CART cell
Description
Serum level of MUC-1 CART cell
Time Frame
Up to approximately 12 months
Title
Related cytokine
Description
Serum level of related cytokine(like IL-2、IL-6、TNF-α、IFNγ and so on)
Time Frame
Up to approximately 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18-65 years old. The expression of ST glycosylated MUC-1 was more than 1+ in immunohistochemistry(IHC) by applicant-approved laboratory. Histopathology or cytology confirmed intrahepatic cholangiocarcinoma. Patients who are unable to perform surgery or are not suitable for surgery, or who have recurrence after surgery, or who are unwilling to undergo chemotherapy. With at least one extracranial measurable lesion according to RECIST 1.1 edition. The expected survival time is more than 60 days. The main organs are functional and meet the following criteria: 1) ECOG physical fitness score was 0~1 or KPS score >70. 2) Routine blood tests were in accordance with the following criteria: HB (>90 g/L) (no blood transfusion within 14 days), ANC (>1.5 x10^9/L), PLT (> 80 x10^9/L), lymphocyte (> 0.7 x10^9/L), LY (> 15%), Alb (> 2.8 g/dL), serum lipase and amylase < 1.5^ULN (upper limit of normal value). 3) Biochemical examination should meet the following criteria: TBIL < 1.5x ULN (upper limit of normal value); ALT < 2.5 xULN; serum Cr<1 xULN; endogenous creatinine clearance > 50ml/min (Cockcroft-Gault formula). 4) Cardiac ejection fraction >55%. 8. No active hemorrhagic disease or severe coagulation dysfunction. 9. No allergy to the contrast media. 10. Women of childbearing age must undergo a pregnancy test (serum or urine) within 7 days before enrollment, and the results are negative, and are willing to use appropriate contraception methods during the experiment and 8 weeks after the last CART. 11. The volunteers voluntarily joined the study, signed informed consent, and had good compliance and follow-up. Exclusion Criteria: The transduction efficiency of T cells was <10% or T cells expanded less than 5 times after culture. Chimeric antigen receptor therapy or other transgenic T cell therapy. Pregnant or lactating women. In the first 4 weeks before the start of the study, they took part in other drug clinical trials. Patients with hypertension who can not be well controlled by a single antihypertensive drug (SBP> 140 mmHg, DBP> 90 mmHg), myocarditis or congenital heart disease, myocardial ischemia or infarction above grade I, arrhythmia above grade I (including QT interval < 440 ms) or cardiac insufficiency. Long term unhealed wounds or fractures. With a history of psychotropic substance abuse and unable to quit or have a history of mental disorders. Past and current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of lung function, etc. With uncontrollable fungi, bacteria, viruses or other infections, or need antibacterial treatment. The presence of simple urinary tract infections and uncomplicated bacterial pharyngitis is allowed after consultation with a medical supervisor, if there is a response to active therapy. According to the NCI-CTCAE 4.0 standard, the patients who had used chemotherapy in the past had grade 2 hematological toxicity or grade 3 non-hematological toxicity. With a history of HIV or hepatitis B or hepatitis C virus infection. There are any indwelling catheters or drainage tubes (e.g. percutaneous nephrostomy, Frey's catheter, bile drainage or pleural/peritoneal/pericardial catheter). The use of dedicated central venous catheters is permitted. With brain metastases. With a history or disease of CNS, such as epileptic seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving CNS. With a major immunodeficiency. The main therapeutic drugs in this study (including fludarabine, cyclophosphamide, sodium mesylate, tropizumab and anti-infective drugs used during pretreatment) had a history of severe hypersensitivity. In the first 6 months of admission, there was a history of deep venous thrombosis or pulmonary embolism. History of autoimmune diseases (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) that cause terminal organ injury or require systemic immunosuppressive/systemic disease-regulating drugs. With any diseases that may interfere with the safety or efficacy of treatment.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tingbo Liang, MD PhD
Phone
8613666676128
Email
liangtingbo@zju.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Qi Zhang, MD
Phone
8613819137113
Email
zhangqi86@gmail.com
Facility Information:
Facility Name
The second affiliated hospital of Zhejiang University
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310009
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qi Zhang, MD
Phone
8613819137113

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Safety and Efficacy Evaluation of MUC-1 CART in the Treatment of Intrahepatic Cholangiocarcinoma

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