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)

Official 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

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 11 participants

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 ce
• 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 sep
• 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).

Primary Outcomes

• Dose limiting toxicities at 6 weeks post T cell infusion (6 weeks after infusion of the last dose of iC9-GD2 T cells to all patients on the study)

Secondary Outcomes

• To evaluate the expansion and persistence of 3rd generation iC9-GD2 T cells (15 years)
• Time to progression of disease (15 years)
• Change in serum cytokine and chemokine levels (15 years)

Eligibility Criteria

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

Trial Locations

• Houston Methodist Hospital, Houston, Texas, United States
• Texas Children's Hospital, Houston, Texas, United States

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