Clinical trial NCT03884751: Chimeric Antigen Receptor T Cells Targeting Glypican-3
Official title: A Phase I Clinical Study of Chimeric Antigen Receptor T Cells Targeting Glypican-3 (CAR-GPC3 T Cells) in Patients With Advanced Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma
CAR-T
Lead sponsor: CARsgen Therapeutics Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: NanJing PLA 81 Hospital
name: First Affiliated Hospital of Zhejiang University
name: RenJi Hospital
First posted: 2019-03-21
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A Phase I Clinical Study of Chimeric Antigen Receptor T Cells Targeting Glypican-3 (CAR-GPC3 T Cells) in Patients with Advanced Hepatocellular Carcinoma

Detailed description: This is a phase I open-label, single-arm, multicenter clinical trial designed to observe and evaluate the safety, cell metabolokinetics, and efficacy of CAR-GPC3 T cells infused intravenously at single escalating doses in patients with advanced hepatocellular carcinoma.

Primary objectives:

- To evaluate the safety and tolerability of CAR-GPC3 T cells infused intravenously at escalating doses in patients with advanced hepatocellular carcinoma.

Secondary objectives：

* To evaluate the metabolic kinetics of single infusion of CAR-GPC3 T cells
* To evaluate the overall safety and tolerability of infusion of CAR-GPC3 T cells
* To observe the efficacy of CAR-GPC3 T cells in the treatment of advanced hepatocellular carcinoma

Eligibility criteria: Inclusion Criteria:

1. Aged 18 to 70 years, male or female;
2. Patients with advanced hepatocellular carcinoma (HCC) diagnosed by histopathology or cytology who are not suitable for surgery or local treatment (including ablation, intervention, and radiotherapy), have developed progressive disease or intolerability after standard systemic therapies (including but not limited to systemic chemotherapy, molecular targeted therapy) and have no effective treatment at the time of enrollment;
3. According to RECIST 1.1, patients have at least one evaluable target lesion, defined as: the longest diameter of non-lymph node lesion ≥ 10 mm, or the shortest diameter of lymph node lesion ≥ 15 mm); hepatic lesions require arterial phase contrast enhancement;
4. In tumor tissue samples GPC3 is detected positive by immunohistochemistry (IHC);
5. According to Barcelona Clinic Liver Cancer staging(BCLC), the patients are classified into Grade C or Grade B unsuitable for local treatment/progressive disease after local treatment;
6. Expected survival is \> 12 weeks;
7. Cirrhosis status Child-Pugh score: Grade A;
8. Eastern Cooperative Oncology Group(ECOG) Performance Status score: 0 to 1 point;
9. Without active hepatitis B and/or Hepatitis C;
10. Have venous accesses for pheresis;
11. Acceptable routine blood test showing no contraindication to the lymphodepletion pretreatment;
12. Adequate liver, renal, cardiovascular, respiratory function;
13. Subjects of childbearing age must undergo a serum pregnancy test within 14 days before the initiation of the study and the result must be negative. In addition, they should be willing to use a reliable method of contraception during the trial (within 24 months (M24) after cell infusion); male subjects whose spouses are women of childbearing age should undergo sterilization surgery or agree to use a reliable method of contraception during the trial;
14. Understand and sign informed consent.

Exclusion Criteria:

1. Pregnant or breast-feeding women;
2. HCV-RNA(Hepatitis C Virus RNA ), HIV antibodies or Syphilis Serological tests are positive;
3. HBV（Hepatitis B） and HCV(Hepatitis C virus ) infection exist simultaneously;
4. Any uncontrollable active infection
5. Patients who had received systemic steroids or other immunosuppressive agents
6. Previous or present hepatic encephalopathy;
7. Current clinically significant ascites;
8. ≥50% of the liver is replaced by tumor or portal vein main tumor thrombus, or tumor thrombus invasion of mesenteric vein / inferior vena cava;
9. Metastases to the central nervous system and clinically significant central nervous system diseases;
10. Patients with existing heart disease in need of treatment or hypertension that be poorly controlled
11. Patients with known active autoimmune diseases which require to be treated with immunosuppressive agents including biological agents;
12. Patients with a history of organ transplantation or waiting for organ transplantation (including liver transplantation);
13. Patients with local treatments such as surgical treatment, interventional therapy, radiotherapy, ablation or systemic chemotherapy were performed for the studied disease within 2 weeks prior to apheresis;Or received immunotherapy (PD-1/ PD-L1 monoclonal antibody, see Section 15) or any Chinese herbal or proprietary medicine for the control of liver cancer within 1 week prior to apheresis;Or received sorafenib, regofenib, ramvastinib and other tyrosine kinase inhibitor targeted drugs within 1 week prior to apheresis;Targeted therapy with anti-angiogenic monoclonal antibodies such as bevacizumab or its analogue 4 weeks prior to apheresis;
14. Patiens with previous treatment with targeted GPC3, TCR-T or CAR-T;
15. Patients who previously received anti-PD-1/ PD-L1 monoclonal antibody therapy within 4 weeks prior to apheresis;
16. Patients who had uncured malignant tumors in the past 5 years or at the same time, excluding in situ cervical cancer and skin basal cell carcinoma;
17. Other serious illnesses that may limit subjects to participate in the trial (such as poorly controlled diabetes mellitus, severe cardiac insufficiency , myocardial infarction or unstable arrhythmia or unstable angina pectoris within the last 6 months, lung embolism, chronic obstructive pulmonary diseases, interstitial pulmonary diseases,gastric ulcer, a history of gastrointestinal bleeding or a clear tendency to gastrointestinal bleeding;
18. According to the investigators' evaluation, patients are unable or unwilling to comply with the requirements of the study protocol.

Primary outcomes:
measure: Dose-limiting toxicity (DLT)
timeFrame: After 28 days of single infusion
measure: Maximum tolerated dose (MTD)
timeFrame: After 28 days of single infusion
Secondary outcomes:
measure: Pharmacokinetics (the copies of cells in vivo)
timeFrame: Day0~Week 26
measure: Pharmacokinetics ( the duration of survival of cells in vivo)
timeFrame: Day0~Week 26
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: Month 24
measure: Antitumor efficacy-Progression-free survival (PFS)
timeFrame: Month 24
measure: Antitumor efficacy-Duration of response (DOR)
timeFrame: Month 24
measure: Antitumor efficacy-Duration of disease control (DDC)
timeFrame: Month 24
measure: Antitumor efficacy-Overall survival (OS)
timeFrame: Month 24
measure: Antitumor efficacy-Objective response rate (ORR);
timeFrame: Month 24
measure: Antitumor efficacy-Disease control rate (DCR)
timeFrame: Month 24
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Nanjing
country: China
facility: The 81st Hospital of Chinese PLA
state: Jiangsu
city: Shanghai
country: China
facility: Renji Hospital Shang Hai Jiaotong Unversity of Medicine
state: Shanghai
city: Shanghai
country: China
facility: Zhongshan Hospital of Fudan University
state: Shanghai
city: Hangzhou
country: China
facility: The First Affiliated Hospital Zhejiang University
state: Zhejiang
Study officials:
affiliation: The 81st Hospital of PLA
name: Qin shukui, Pro
role: PRINCIPAL_INVESTIGATOR
affiliation: RenJi Hospital
name: Zhai bo, Pro
role: PRINCIPAL_INVESTIGATOR
References: