GPC3-directed CAR-T in the Treatment Amongst Subjects With Advanced Hepatocellular Carcinoma
Study Details
Study Description
Brief Summary
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and efficacy of infused autologous armored GPC3-directed CAR-T in patients with advanced hepatocellular carcinoma refractory to prior systematic treatments.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CAR-GPC3 T cells The safety and efficacy of JWATM214 will be evaluated in a 'BOIN'-designed dose escalation approach. 3 CAR-T dose levels will be tested in this study: 1×10^8, 3×10^8, and 10×10^8, whereas the dosage 0.5×10^8 and 30×10^8 CAR-T cells will be selected as optional back-up doses for potential escalation or de-escalation. |
Biological: CAR-GPC3 T cells
Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JWATM214 . During JWATM214 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 JWATM214 by intravenous (IV) injection.
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Outcome Measures
Primary Outcome Measures
- Treatment-related adverse events (AEs) [2 years]
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.
- Dose-limiting toxicities [28 days]
DLT (Dose-limiting toxicity) was an adverse event that occurred within 28 days after JWATM214 infusion that met any of the following criteria. Any grade ≥3 nonhematologic toxicity associated with JWATM214 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.
- RP2D of JWATM214 in HCC patients [2 years]
Recommended phase 2 dose of JWATM214
Secondary Outcome Measures
- PK of JWATM214 in the peripheral blood (qPCR) [1 years]
The pharmacokinetic parameters of JWATM214 will be evaluated by qPCR for the copy number of the vector transgene of JWATM214 in peripheral blood to evaluate T-cell expansion and persistence.
- Objective response rate (ORR). [1 years]
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.
- Disease Control Rate [2 years]
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.
- progression-free survival (PFS) [2 years]
Defined as time from randomisation to first progression by investigator assessment using modified RECIST 1.1 or death (by any cause in the absence of progression)
- overall survival (OS) [2 years]
Defined as the time from randomisation to death due to any cause
Eligibility Criteria
Criteria
Inclusion Criteria:
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18-75 years-old, male or female
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Voluntarily willing to participate in the study and sign the written informed consent form
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Life expectation ≥12 weeks
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Eastern Cooperative Oncology Group (ECOG) performance status scale ≤1
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Histologically-confirmed hepatocellular carcinoma (HCC)
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No benefits from curative surgery or other local therapies are expected at screening, judged by investigators
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Radiologically-confirmed progression disease after at least one prior line of systematic treatment and limited benefits from current guideline or consensus for hepatocellular carcinoma are expected at screening, judged by investigators
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Fresh samples or FFPE, immunohistochemistry (IHC)-stained GPC-3 positive with intensity ++ or +++
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Per RECIST v1.1, at least one measurable lesion
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Manageable lung metastasis
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Barcelona Clinic Liver Cancer (BCLC) stage C or B and Child-Pugh ≤7
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No active HBV infections
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Adequate organ functions
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Adequate venous access for APH
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Non-hematological AEs induced by previous treatment must have recovered to CTCAE ≤1, except for alopecia and peripheral neuropathy
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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
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Women of childbearing potential must have negative serum β-hCG test result at screening and 48 hours prior to lymphodepletion
Exclusion Criteria:
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Cholangiocarcinoma or histological-mixed hepatocellular cholangiocarcinoma
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Active brain metastasis
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Primary lesion or infused lesions with the longest diameter ≥15cm, or other potential risk which might not be appropriate for further study treatment judged by the investigator
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Another primary malignancy within 3 years (with some exceptions for completely-resected early-stage tumors)
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Systematic autoimmune disorders requiring long-term systematic immunosuppression
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Previously treated with any genetically engineered modified T cell therapy (TCR-T/CAR-T) or other CGT
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Active HCV, HIV, or syphilis
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History of organ transplant
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Uncontrolled or active infection at screening, prior to APH, 72 hours prior to lymphodepletion or 5 days prior to JWATM214 infusion
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With severe cardiovascular disease
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History or presence of clinically-relevant CNS disorders
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Current presence of hepatic encephalopathy
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≥G2 hemorrhage within 30 days prior to screening, or in need of long-term anticoagulants
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Active digestive ulcer or gastrointestinal bleeding within 3 months prior to screening
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Pregnant or lactating women
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Not satisfying wash-out period for APH
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Unable or unwilling to comply with the study protocol, judged by the investigator
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Other situations implying that the subject might not be appropriate to participate in the study
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Previously allergic or intolerable to JWATM214 or its components
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University | Shanghai | China | 200127 |
Sponsors and Collaborators
- RenJi Hospital
Investigators
- Study Chair: Qiang Xia, Prof. MD, Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU
- Principal Investigator: Hao Feng, MD.,Ph.D., Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- JWATM214001