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ACTIVE NOT RECRUITING

NCT01822652

PHASE1

3rd Generation GD-2 Chimeric Antigen Receptor and iCaspase Suicide Safety Switch, Neuroblastoma, GRAIN

Sponsor: Baylor College of Medicine

View on ClinicalTrials.gov

Summary

Subjects that have relapsed or refractory neuroblastoma are invited to take part in this gene transfer research study. We have found from previous research that we can put a new gene called a chimeric antigen receptor (CAR) into T cells that will make them recognize neuroblastoma cells and kill them. In a previous clinical trial, we used a CAR that recognizes GD2, a protein found on almost all neuroblastoma cells (GD2-CAR). We put this gene into T cells and gave them back to patients that had neuroblastoma. The infusions were safe and in patients with disease at the time of their infusion, the time to progression was longer if we could find GD2 T cells in their blood for more than 6 weeks. Because of this, we think that if T cells are able to last longer, they may have a better chance of killing neuroblastoma tumor cells. Therefore, in this study we will add new genes to the GD2 T cells that can cause the cells to live longer. These new genes are called CD28 and OX40. The purpose of this study will be to determine the highest dose of iC9-GD2-CD28-OX40 (iC9-GD2) T cells that can safely be given to patients with relapsed/refractory neuroblastoma. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and we think that it will allow the T cells we infuse to expand and stay longer in the body, and potentially kill cancer cells more effectively. The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine. Additionally, to effectively kill the tumor cells, it is important that the T cells are able to survive and expand in the tumor. Recent studies have shown that solid tumors release a substance (PD1) that can inhibit T cells after they arrive into the tumor tissue. In an attempt to overcome the effect of PD1 in neuroblastoma we will also give a medication called pembrolizumab.

Official title: Autologous Activated T-Cells Transduced With A 3rd Generation GD-2 Chimeric Antigen Receptor And iCaspase9 Safety Switch Administered To Patients With Relapsed Or Refractory Neuroblastoma (GRAIN)

Key Details

Gender

All

Age Range

Any - Any

Study Type

INTERVENTIONAL

Enrollment

Start Date

2013-08

Completion Date

2030-10

Last Updated

2026-04-06

Healthy Volunteers

Conditions

Neuroblastoma

Interventions

GENETIC

iC9-GD2 T Cells - frozen

Subjects will receive the iC9-GD2 T cells through an IV over 5 to 10 minutes. Subjects will receive one of the following dose levels (cells/m2): * Dose Level 1 = 1 x 10\^7 * Dose Level 2 = 1 x 10\^8 * Dose Level 3 = 2 x 10\^8 Six weeks after the infusion, patients will have a disease re-evaluation. If the disease has not gotten worse AND they have not had a severe side effect caused by the infusion of the iC9-GD2 T cells, the subject may be eligible to receive up to 2 additional doses of T cells. Each dose will be at the same dose level as the first infusion, if available, and separated by at least 6 weeks.

GENETIC

iC9-GD2 T Cells - fresh

For subjects who will receive a fresh T cell product: * Dose Level 1 = 1 x 10\^8 * Dose Level 2 = 1.5 x 10\^8 * Dose Level 3 = 2 x 10\^8 Six weeks after the infusion, patients will have a disease re-evaluation. If the disease has not gotten worse AND they have not had a severe side effect caused by the infusion of the iC9-GD2 T cells, the subject may be eligible to receive up to 2 additional doses of T cells. Each dose will be at the same dose level as the first infusion, if available, and separated by at least 6 weeks.

DRUG

Cytoxan

Cyclophosphamide (500 mg/m2/day x 2 days, for patients \<12 kg = 16.7 mg/kg/day x 2 days)

DRUG

Fludara

Fludarabine (30 mg/m2/day x 3 days, for patients \<12 kg = 1 mg/kg/day x 3 days)

DRUG

Keytruda

Pembrolizumab (2 mg/kg on Day -1 and on Day 21).

GENETIC

iC9-GD2 T cells

For subjects who will receive a fresh T cell product: * Dose Level 1 = 1.5 x 10\^8 * Dose Level 2 = 2 x 10\^8 Six weeks after the infusion, patients will have a disease re-evaluation. If the disease has not gotten worse AND they have not had a severe side effect caused by the infusion of the iC9-GD2 T cells, the subject may be eligible to receive up to 2 additional doses of T cells. Each dose will be at the same dose level as the first infusion, if available, and separated by at least 6 weeks.

Inclusion Criteria: PROCUREMENT * High risk neuroblastoma with persistent or relapsed disease * Life expectancy of at least 12 weeks * Karnofsky/Lansky score of 60% or greater * Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies) * Informed consent and assent (as applicable) obtained from parent/guardian and child TREATMENT: * High risk neuroblastoma with persistent or relapsed disease * Life expectancy of at least 12 weeks * Karnofsky/Lansky score of 60% or greater * Patients must have an ANC greater than or equal to 500, platelet count greater than or equal to 20,000 * Pulse Ox greater than or equal to 90% on room air * AST and ALT less than 5 times the upper limit of normal * Total bilirubin less than 3 times the upper limit of normal * Serum creatinine less than 3 times upper limit of normal. Creatinine clearance is needed for patients with creatinine greater than 1.5 times upper limit of normal * TSH normal for age. Patients using thyroid medication to facilitate a euthyroid state must be on a stable dose for at least 1 month prior to planned infusion * Recovered from acute effects of all prior chemotherapy. If some effects of therapy have become chronic (i.e., treatment associated thrombocytopenia), the patient must be clinically stable and meet all other eligibility criteria * Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who have received prior therapy with murine antibodies * Patients must have autologous transduced activated T-cells with greater than or equal to 20% expression of GD2 * Pembrolizumab available for infusion * Informed consent and assent (as applicable) obtained from parent/guardian and child Exclusion Criteria: PROCUREMENT: * Rapidly progressive disease * History of hypersensitivity to murine protein containing products TREATMENT: * Rapidly progressive disease * Currently receiving other investigational drugs * History of hypersensitivity to murine protein containing products * History of cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT. However, patients with cardiomegaly on imaging may be enrolled if they have an assessment of cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting protocol therapy that is within normal limits. Additionally, patients with bilateral pulmonary infiltrates on imaging may be enrolled if the lesions are not consistent with active neuroblastoma (i.e., negative on functional imaging with PET or MIBG, or by pathologic assessment). * Evidence of tumor potentially causing airway obstruction * Patients who are pregnant, lactating, or unwilling to use birth control * Patients currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine * Patients previously experienced severe toxicity from cyclophosphamide or fludarabine * Severe previous toxicity from pembrolizumab or other PD-1 targeted antibody

Locations (2)

Houston Methodist Hospital

Houston, Texas, United States

Texas Children's Hospital

Houston, Texas, United States

Clinical Research Directory

3rd Generation GD-2 Chimeric Antigen Receptor and iCaspase Suicide Safety Switch, Neuroblastoma, GRAIN

Summary

Key Details

Conditions

Interventions

Eligibility Criteria

Locations (2)