Genetically Engineered Cells (15.GPC3-CAR T Cells) for the Treatment of Relapsed or Refractory Solid Tumors, AGAR Trial

Status: active

This phase I trial tests the safety, side effects, and best dose of 15.GPC3-CAR T cells in treating patients with solid tumors that have come back (recurrent) or do not respond to treatment (refractory). 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. Adding a new gene (a tiny part of what makes-up deoxyribonucleic acid [DNA] and carries traits) into T cells may help them recognize cancer cells and kill them. The antibody GC33 recognizes a protein found on solid tumors. IL15 is a protein that helps chimeric antigen receptor (CAR) T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 may kill tumor cells better compared with CAR T cells that do not have IL15. This trial may help researchers determine if T cells that have been made (called genetic engineering) with the IL15 GPC3-CAR (AGAR T cells) work to kill tumor cells in patients with GPC3-positive solid tumors.

Inclusion Criteria

PROCUREMENT: Relapsed or refractory GPC3-positive solid tumors (as determined by immunohistochemistry with an extent score of >= grade 2 [> 25% positive tumor cells] and an intensity score of >= 2 [scale 0-4]) * GPC3 expression will be evaluated by standard immunohistochemistry (IHC) at Texas Children’s Hospital/Baylor College of Medicine, Department of Pathology for all patients to meet procurement eligibility. All patients will send at least 5 unstained slides
PROCUREMENT: Age >= 1 year and =< 21 years
PROCUREMENT: Lansky or Karnofsky score >= 60%
PROCUREMENT: Life expectancy >= 16 weeks
PROCUREMENT: Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only)
PROCUREMENT: Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only)
PROCUREMENT: Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
TREATMENT: Age >= 1 year and =< 21 years
TREATMENT: Barcelona Clinic Liver Cancer stage A, B or C (for patients with hepatocellular carcinoma only)
TREATMENT: Life expectancy of >= 12 weeks
TREATMENT: Lansky or Karnofsky score >= 60%
TREATMENT: Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only)
TREATMENT: Creatinine clearance as estimated by Cockcroft Gault or Schwartz >= 60 ml/min
TREATMENT: Serum aspartate aminotransferase (AST) < 5 times upper limit of normal (ULN)
TREATMENT: Total bilirubin < 3 times ULN for age
TREATMENT: International normalized ratio (INR) =< 1.7 (for patients with hepatocellular carcinoma only)
TREATMENT: Absolute neutrophil count > 500/ul
TREATMENT: Platelet count > 25,000/ul (can be transfused)
TREATMENT: Hemoglobin (Hgb) >= 7.0 g/dl (can be transfused)
TREATMENT: Pulse oximetry > 90% on room air
TREATMENT: Refractory or relapsed disease after treatment with up- front therapy and at least one salvage treatment cycle
TREATMENT: Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study
TREATMENT: Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion
TREATMENT: Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria

PROCUREMENT: 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)
PROCUREMENT: History of organ transplantation
PROCUREMENT: Known human immunodeficiency virus (HIV) positivity
PROCUREMENT: Active bacterial, fungal or viral infection (except hepatitis B or hepatitis C virus infections)
TREATMENT: Pregnancy or lactation
TREATMENT: Uncontrolled infection
TREATMENT: Systemic steroid treatment (>= 0.5 mg prednisone equivalent/kg/day, dose adjustment or discontinuation of medication must occur at least 24 hours [hrs] prior to CAR T cell infusion)
TREATMENT: Known HIV positivity
TREATMENT: Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
TREATMENT: History of organ transplantation
TREATMENT: 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)

PRIMARY OBJECTIVE:

I. To determine the safety of escalating doses of an intravenous injection of autologous anti-glypican-3 CAR-IL-15-iC9-expressing T-lymphocytes (15.GPC3-CAR T cells) in children with GPC3-positive solid tumors after lymphodepleting chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of 15.GPC3-CAR T cells in treating patients with GPC3-positive solid tumors after lymphodepleting chemotherapy.

II. To assess the anti-tumor effect of infused 15.GPC3-CAR T cells in children with GPC3-positive solid tumors.

EXPLORATORY OBJECTIVE:

I. To assess the in vivo persistence, phenotype and functional activity of infused 15.GPC3-CAR T cells in children with GPC3-positive solid tumors.

OUTLINE: This is a dose-escalation study of 15.GPC3-CAR T cells.

Patients receive cyclophosphamide intravenously (IV) over 1 hour and fludarabine IV over 30 minutes on days -4 to -2. Patients also receive 15.GPC3-CAR T cells IV over 5-10 minutes on days 1-2.

After completion of study treatment, patients are followed up every 6 months for 4 years and the annually for up to 15 years.

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Genetically Engineered Cells (15.GPC3-CAR T Cells) for the Treatment of Relapsed or Refractory Solid Tumors, AGAR Trial

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Exclusion Criteria

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Genetically Engineered Cells (15.GPC3-CAR T Cells) for the Treatment of Relapsed or Refractory Solid Tumors, AGAR Trial

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