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T Cells co- Expressing a Second Generation Glypican 3-specific Chimeric Antigen Receptor With Cytokines Interleukin-21 and 15 as Immunotherapy for Patients With Liver Cancer (TEGAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04093648
Recruitment Status : Withdrawn (The key elements of this study were incorporated into another study.)
First Posted : September 18, 2019
Last Update Posted : May 20, 2020
Sponsor:
Collaborator:
The Methodist Hospital System
Information provided by (Responsible Party):
Andras Heczey, Baylor College of Medicine

Brief Summary:

This study is for patients that have a type of cancer that arises from the liver, either called hepatocellular carcinoma or hepatoblastoma. The cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study will use special immune system cells called TEGAR T cells, a new experimental treatment.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise but have not been strong enough to cure most patients. The investigator found from preclinical research that they can put a new gene into T cells that will help them recognize cancer cells and kill them. In our preclinical studies, several genes were made called a chimeric antigen receptor (CAR), from an antibody called GC33 that recognizes glypican-3, a protein found on almost all hepatocellular carcinoma cells and hepatoblastoma cells (GPC3-CAR). In the laboratory the investigators have been doing research into GPC3-CAR cells. They have selected the GPC3-CAR with the strongest ability to recognize hepatocellular carcinoma or hepatoblastoma cells for this study. This is a safety study where the investigator will be testing the ability of GPC3-CAR cells to identify and kill tumor cells in patients. The investigators also tested the effects of adding the molecule interleukin-15 (IL-15) alone or with another molecule called interleukin-21. The investigators found that IL-15 alone or together with IL-21 can help GPC3-CAR T cells last longer which helps them to kill more tumor cells. In this study the investigator will be testing the ability of GPC3-CAR cells to identify and kill tumor cells in patients. This is a study looking at safety and the investigators will therefore be starting with GPC3-CAR T cells alone in a set of patients. The first set of patients will receive GPC3-CAR T cells that also express IL-15. In the second group, the investigators will evaluate GPC3-CAR T cells that express both IL-15 and IL-21. If the investigators are able to safely give GPC3- CAR T cells, they will increase the dose of the combination cells in other patients. The product or dose level of cells that the participant will receive is based on when they are enrolled on the study.

The GPC3-CAR T cells are an investigational product not approved by the Food and Drug Administration.

The purpose of this study is to find the biggest dose of GPC3-CAR T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the GPC3-CAR T cells will help people with GPC3-positive hepatocellular carcinoma or hepatoblastoma.


Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Hepatoblastoma Genetic: TEGAR T cells Drug: Cytoxan Drug: Fludarabine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: T Cells co- Expressing a Second Generation Glypican 3-specific Chimeric Antigen Receptor With Cytokines Interleukin-21 and 15 as Immunotherapy for Patients With Liver Cancer
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : January 2038

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer

Arm Intervention/treatment
Experimental: TEGAR T cells + Fludarabine and Cytoxan
GPC3-CAR (TEGAR T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with hepatocellular carcinoma.
Genetic: TEGAR T cells

Five different dosing schedules will be evaluated. Three to six patients will be evaluated on each dosing schedule. The following dose levels will be evaluated:DL1: 1x10^7/m2 DL2: 3x10^7/m2 DL3: 1x10^8/m2 DL4: 3x10^8/m2 DL5: 1x10^9/m2 If DLTs are observed on DL1, patients will be enrolled on DL0 at 3x10^6/m2 dose.

The first patient on each dose level has to be 28 days post-CAR T cell infusion before the second patient can be enrolled. The doses are calculated according to the actual number of GPC3-CAR transduced T cells.

Other Name: GPC3-CAR T cells

Drug: Cytoxan
Cyclophosphamide will be given at a dose of 500 mg/m2/day for 3 days given intravenously
Other Name: Cyclophosphamide

Drug: Fludarabine
Fludarabine will be given at a dose of 30 mg/m2/day for 3 days given intravenously




Primary Outcome Measures :
  1. Dose Limiting Toxicity (DLT) Rate [ Time Frame: Start of lymphodepleting chemotherapy to 4 weeks post T cell infusion ]
    1. DLT rate will be calculated as the number of patients experiencing a DLT divided by the total number of patients receiving treatment.
    2. The NCI Common Toxicity Criteria V5.X will be used in grading toxicity with the exception of CRS and neurological toxicities that are related to T-cell infusions. CRS and neurological toxicities will be graded according to Appendix VI in the protocol.


Secondary Outcome Measures :
  1. Response Rate according [ Time Frame: 8 weeks post T-cell infusion ]
    Response rate will be estimated as the percent of patients whose best response is either complete remission or partial remission using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee and by the Immune-related Response Criteria.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Procurement Eligibility

Inclusion Criteria:

  • Histology-proven hepatocellular carcinoma (HCC) which is unresectable, recurrent and/or metastatic OR recurrent or resistant hepatoblastoma (HB)
  • Barcelona Clinic Liver Cancer Stage A, B or C
  • GPC3-positive HCC or HB
  • Age ≥ 1 years
  • Karnofsky score >60% (See appendix I)
  • Life expectancy >12 weeks
  • Child-Pugh-Turcotte score <7 (for patients with cirrhosis only)
  • Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria:

  • Heart failure of Class II-IV and / or B-D per NYHA Criteria
  • History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies)
  • History of liver transplantation
  • Known HIV positivity
  • Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
  • Severe previous toxicity from cyclophosphamide or fludarabine

Treatment Eligibility

Inclusion Criteria:

  • Histology-proven HCC which is unresectable, recurrent and/or metastatic or relapsed / refractory HB
  • Barcelona Clinic Liver Cancer Stage A, B or C
  • GPC3-positive HCC or HB
  • Age ≥ 1 years
  • Life expectancy of ≥ 12 weeks
  • Karnofsky score ≥ 60%
  • Child-Pugh-Turcotte score < 8
  • Adequate organ function:
  • clearance (as estimated by Cockcroft Gault) ≥ 60 ml/min
  • serum AST< 5 times ULN
  • total bilirubin < 3 times ULN for age
  • INR ≤1.7
  • absolute neutrophil count > 500/microliter
  • platelet count > 20,000/microliter (can be transfused)
  • Hgb ≥9.0 g/dl (can be transfused)
  • Pulse oximetry >90% on room air
  • Recovered from acute toxic effects of all prior chemotherapy before entering this study
  • Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
  • Available autologous transduced CAR T cells
  • Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria:

  • Pregnancy or lactation (for women at child-bearing age, birth control is required)
  • Receiving investigational drugs within 2 weeks prior to treatment
  • Hepatic encephalopathy
  • Uncontrolled infection
  • Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day)
  • Known HIV positivity
  • Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
  • History of liver transplantation
  • Heart failure of Class II-IV and / or B-D per NYHA Criteria
  • History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies)
  • Severe previous toxicity from cyclophosphamide or fludarabine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04093648


Sponsors and Collaborators
Baylor College of Medicine
The Methodist Hospital System
Investigators
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Principal Investigator: Andras Heczey, MD Baylor College of Medicine
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Responsible Party: Andras Heczey, Assistant Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT04093648    
Other Study ID Numbers: H-43874 TEGAR
First Posted: September 18, 2019    Key Record Dates
Last Update Posted: May 20, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andras Heczey, Baylor College of Medicine:
Hepatocellular Carcinoma
Hepatoblastoma
GPC3-CAR T cells
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Liver Neoplasms
Hepatoblastoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Neoplasms, Complex and Mixed
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists