A Phase 1, Single-arm, Open-label, Dose-escalation Study of JWATM204 as T Cell-targeted Immunotherapy in the Treatment Amongst Subjects With Advanced Hepatocellular Carcinoma

This is a single arm, open-label, dose escalation clinical study to evaluate the safety and efficacy of infused autologous GPC3-directed CAR-T in patients with advanced hepatocellular carcinoma refractory to prior systematic treatments.

Study Overview

• Status: Recruiting
• Conditions: Liver Carcinoma; Hepatic Cell Carcinoma
• Intervention / Treatment: Biological: CAR-GPC3 T cells

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Tao Zhang, MD, PhD; Phone Number: +86 027-85726375; Email: 1277577866@qq.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Tao Zhang
      • Contact: Tao Zhang, MD, PhD
      • Principal Investigator: Tao Zhang, MD, PhD
      • Sub-Investigator: Jun Xue, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-75 years-old, male or female
2. Voluntarily willing to participate in the study and sign the written informed consent form
3. Life expectation ≥12 weeks
4. Eastern Cooperative Oncology Group (ECOG) performance status scale ≤1
5. Histologically-confirmed hepatocellular carcinoma (HCC)
6. No benefits from curative surgery or other local therapies are expected at screening, judged by investigators
7. Radiologically-confirmed progression disease after at least one prior line of systematic treatment and limited benefits from current available options for hepatocellular carcinoma are expected at screening, judged by investigators
8. Fresh samples or formalin-fixed paraffin-embedded (FFPE) samples, immunohistochemistry (IHC)-stained GPC-3 positive
9. Per RECIST v1.1, at least one measurable lesion
10. Barcelona Clinic Liver Cancer (BCLC) stage C or B and Child-Pugh ≤7
11. No active infections of hepatitis B virus
12. Adequate organ functions
13. Adequate venous access for apheresis
14. Non-hematological AEs induced by previous treatment must have recovered to CTCAE ≤1, except for alopecia and peripheral neuropathy
15. Women of childbearing potential must agree to use an effective and reliable contraceptive method during 28 days prior to lymphodepletion to 1 year post infusion; Male patients who have not undergone vasectomy and have sexual activity with women of childbearing potential must agree to the use of a barrier contraceptive method since lymphodepletion to 1year post infusion, and sperm donation is prohibited during the study
16. Women of childbearing potential must have negative serum β-human chorionic gonadotropin (β-hCG) test result at screening and 48 hours prior to lymphodepletion

Exclusion Criteria:

1. Active brain metastasis
2. Primary lesion or infused lesions with the longest diameter ≥15 cm, or other potential risk which might not be appropriate for further study treatment judged by the investigator
3. Another primary malignancy within 3 years (with some exceptions for completely-resected early-stage tumors)
4. Systematic autoimmune disorders requiring long-term systematic immunosuppression
5. Previously treated with any genetically engineered modified T-cell therapy nor other cell-gene therapy
6. Active infections of hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis
7. Uncontrolled or active infection at screening, prior to apheresis, 72 hours prior to lymphodepletion or 5 days prior to JWATM204 infusion
8. With severe cardiovascular disease History or presence of clinically-relevant central nervous system (CNS) disorders
9. With clinically-significant CNS disorders
10. Current presence of or previously with hepatic encephalopathy
11. ≥G2 hemorrhage within 30 days prior to screening, or in need of long-term anticoagulants
12. Pregnant or lactating women
13. Not satisfying pre-defined wash-out period for apheresis
14. Received plasma exchange within 14 days prior to apheresis
15. Unable or unwilling to comply with the study protocol, judged by the investigator, or other situations implying that the subject might not be appropriate to participate in the study
16. Vaccinated with live vaccinations against infectious diseases within 8 weeks prior to JWATM204 infusion
17. Previously allergic or intolerable to JWATM204 or its components

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: CAR-GPC3 T cells; The safety and efficacy of JWATM204 will be evaluated in a Bayesian Optimal Interval Design (BOIN) dose escalation approach. 3 CAR-T dose levels will be tested in this study: 1×10^8, 3×10^8, 10×10^8, and 30×10^8 CAR-T cells will be explored.

Biological: CAR-GPC3 T cells; Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JWATM204 . During JWATM204 production, subjects will receive a preconditioning chemotherapy regimen of cyclophosphamide and fludarabine to deplete the lymphocytes. After lymphodepletion, subjects will receive single-dose treatment with JWATM204 by intravenous (IV) injection.; Other Names: JWCAR204

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of dose-limiting toxicities (DLTs)	Dose-limiting toxicity (DLT) is defined as an adverse event that occurred within 28 days after JWATM204 infusion that met any of the following criteria. Any grade ≥3 nonhematologic toxicity associated with JWATM204 that has not resolved to ≤ grade 2 within 7 days, excluding clinically insignificant abnormalities in laboratory indicators Hematologic toxicity Grade ≥3 anaphylaxis Grade ≥3 infection did not resolve to grade ≤2 within 7 days after anti-infective treatment. ≥ grade 3 autoimmune toxicity during treatment Grade ≥3 cytokine release syndrome (CRS) during treatment that did not resolve to grade ≤2 within 72 hours. Grade ≥3 CAR-T cell-associated encephalopathy syndrome/immune effector cell-associated neurotoxicity syndrome (CRES/ICANS) that did not resolve to grade ≤2 within 72 hours. Grade 5 events of any nonmalignant cause.	28 days
Rate and severity of adverse events (AEs) and severe adverse events (SAEs)	An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.	2 years
Rate and severity of clinically-significant abnormalities in laboratory testings	Clinically-significant abnormalities in laboratory testings.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Copy number of the vector transgene of JWATM204 in peripheral blood	The pharmacokinetic parameters of JWATM204 will be evaluated by quantitative polymerase chain reaction (qPCR) for the copy number of the vector transgene of JWATM204 in peripheral blood to evaluate T-cell expansion and persistence.	1 year
Objective response rate (ORR)	Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.	2 years
Disease Control Rate (DCR)	The percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents.	2 years
Progression-free survival (PFS)	Defined as time from randomisation to first progression by investigator assessment using revised Response Evaluation Criteria in Solid Tumours (RECIST) guidelines (version 1.1) or death (by any cause in the absence of progression)	2 years
Overal survival (OS)	Defined as the time from randomisation to death due to any cause.	2 years

Collaborators and Investigators

• Sponsor: Shanghai Ming Ju Biotechnology Co., Ltd.
• Investigators: Principal Investigator: Tao Zhang, MD, PhD, Wuhan Union Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2022
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 15, 2023
• First Submitted That Met QC Criteria: November 20, 2023
• First Posted (Actual): November 22, 2023

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 27, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: JWATM204001

Drug and device information, study documents

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