Autologous Glypican-3 Specific Chimeric Antigen Expressing T Cells Co-Expressing IL-15 and IL21 and Lymphodepleting Chemotherapy for the Treatment of Patients with Relapsed or Refractory GPC3-Positive Solid Tumors

Status: active

This phase I trial tests the safety, side effects and best dose of autologous glypican-3 specific chimeric antigen expressing T cells co-expressing IL-15 and IL21 and lymphodepleting chemotherapy for the treatment of patients with GPC3-positive solid tumors that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Lymphodepleting chemotherapy, with cyclophosphamide and fludarabine, is given to kill any remaining cancer cells and prepare the body to receive the CAR t-cells. Giving autologous glypican-3 specific chimeric antigen expressing T cells co-expressing IL-15 and IL21 with lymphodepleting chemotherapy may be safe, tolerable and/or effective in treating patients with relapsed or refractory GPC3-positive solid tumors.

Inclusion Criteria

PROCUREMENT: Diagnosis of 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 Patients’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 ≥ 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: Diagnosis of GPC3-positive solid tumor
TREATMENT: Age ≥ 21 years
TREATMENT: Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only)
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: Total bilirubin < 3 times upper limit of normal (ULN) for age
TREATMENT: International Normalized Ratio (INR) ≤ 1.7 (for patients with hepatocellular carcinoma only)
TREATMENT: Absolute neutrophil count > 500/µl
TREATMENT: Platelet count > 25,000/µl (can be transfused)
TREATMENT: Hemoglobulin (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, as determined by history and physical exam
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 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 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 IL-15/IL-21-armored anti-glypican-3 CAR T-cells (21.15.GPC3-CAR T cells) in patients with GPC3-positive solid tumors after lymphodepleting chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of 21.15.GPC3-CAR T cells in treating patients with GPC3-positive solid tumors after lymphodepleting chemotherapy.

II. To assess the anti-tumor effect of infused 21.15.GPC3-CAR T cells in patients with GPC3-positive solid tumors.

EXPLORATORY OBJECTIVE:

I. To assess the in vivo persistence, phenotype and functional activity of infused 21.15.GPC3-CAR T cells in patients with GPC3-positive solid tumors.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) over 1 hour and fludarabine IV over 30 minutes on days -4 to -2 and 21.15.GPC3-CAR T cells IV on day 0 to +2 of each cycle in the absence of disease progression or unacceptable toxicity. Patients with a response or at least stable disease at 4 weeks and no dose limiting toxicity with the first treatment may receive up to 3 additional cycles. Patients undergo tumor biopsy on study and computed tomography (CT) scan or magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up weeks 1-4, week 8, every 3 months for 1 year, every 6 months for 4 years then yearly for a total of 15 years.

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Autologous Glypican-3 Specific Chimeric Antigen Expressing T Cells Co-Expressing IL-15 and IL21 and Lymphodepleting Chemotherapy for the Treatment of Patients with Relapsed or Refractory GPC3-Positive Solid Tumors

Inclusion Criteria

Exclusion Criteria

United States

Texas

Houston

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Autologous Glypican-3 Specific Chimeric Antigen Expressing T Cells Co-Expressing IL-15 and IL21 and Lymphodepleting Chemotherapy for the Treatment of Patients with Relapsed or Refractory GPC3-Positive Solid Tumors

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