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)

NCT04093648 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: H-43874 TEGAR
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Hepatocellular Carcinoma; Hepatoblastoma

Keywords

Hepatocellular Carcinoma; Hepatoblastoma; GPC3-CAR T cells

Outcome Measures

Primary Outcomes (1)

• Dose Limiting Toxicity (DLT) Rate

  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.

  Start of lymphodepleting chemotherapy to 4 weeks post T cell infusion

Secondary Outcomes (1)

• Response Rate according

  8 weeks post T-cell infusion

Study Arms (1)

TEGAR T cells + Fludarabine and Cytoxan

EXPERIMENTAL

GPC3-CAR (TEGAR T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with hepatocellular carcinoma.

Genetic: TEGAR T cells; Drug: Cytoxan; Drug: Fludarabine

Interventions

TEGAR T cells GENETIC

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.

Also known as: GPC3-CAR T cells

TEGAR T cells + Fludarabine and Cytoxan

Cytoxan DRUG

Cyclophosphamide will be given at a dose of 500 mg/m2/day for 3 days given intravenously

Also known as: Cyclophosphamide

TEGAR T cells + Fludarabine and Cytoxan

Fludarabine DRUG

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

TEGAR T cells + Fludarabine and Cytoxan

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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:

Sponsors & Collaborators

• Baylor College of Medicine: lead
• The Methodist Hospital Research Institute: collaborator

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Hepatoblastoma

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Neoplasms, Complex and Mixed

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Andras Heczey, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 16, 2019
• First Posted: September 18, 2019
• Study Start: January 1, 2020
• Primary Completion: February 1, 2023
• Study Completion (Estimated): January 1, 2038
• Last Updated: May 20, 2020

Record last verified: 2020-05