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

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.

Study Overview

• Status: Recruiting
• Conditions: Intrahepatic Cholangiocarcinoma
• Intervention / Treatment: Biological: MUC-1 CART cell immunotherapy

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.

• Study Type: Interventional
• Enrollment (Anticipated): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • Recruiting
      • The Second Affiliated Hospital of Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MUC-1 CART; 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.	Biological: MUC-1 CART cell immunotherapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate	Percentage of patients whose cancer doesn't progress after treatment	Up to approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Percentage of patients whose cancer shrinks or disappears after treatment	Up to approximately 12 months
Duration of overall response	The time of initial response until documented tumor progression.	Up to approximately 12 months
Progression-free survival	The percentage of people does not get worse for a period of time after diagnosis	Up to approximately 12 months
Overall survival	The percentage of people still alive for a given period of time after diagnosis	Up to approximately 12 months
Common Toxicity Criteria for Adverse Effects	According to Common Toxicity Criteria for Adverse Effects version 4	Up to approximately 12 months
EORTC QLQ - PAN26	Assessed by the European Organization for Research and Treatment of Cancer Quality of Life	Up to approximately 12 months
Anti-MUC1 CART cell antibody	Serum level of anti-MUC1 CART cell antibody	Up to approximately 12 months
MUC1 CART cell	Serum level of MUC-1 CART cell	Up to approximately 12 months
Related cytokine	Serum level of related cytokine(like IL-2、IL-6、TNF-α、IFNγ and so on)	Up to approximately 12 months

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Anticipated): August 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: August 14, 2018
• First Submitted That Met QC Criteria: August 14, 2018
• First Posted (Actual): August 16, 2018

Study Record Updates

• Last Update Posted (Actual): August 22, 2018
• Last Update Submitted That Met QC Criteria: August 20, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: CAR-T; Immunotherapy; ICC; Mucin-1
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma
• Other Study ID Numbers: SAHZJU-Y2018-078

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No