Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	over 1 to under 21	NCI	NCI-90-C-210B NCI-T90-0110N, T90-0110

Objectives

I.  Determine the therapeutic activity of interleukin-2 (IL-2) plus tumor 
infiltrating lymphocytes (TIL) and interferon gamma (IFN-G) in children with 
advanced neuroblastoma (the therapeutic activity of IL-2/IFN-G will be 
determined in patients for whom TIL cannot be successfully expanded).

II.  Determine, in a limited number of patients, the feasibility of generating 
TIL from peripheral tumor sources (e.g., infiltrated bone marrow) to examine 
the following:  in vitro growth kinetics and cytokine requirements of TIL 
derived from solid tumor vs. bone marrow; immunophenotypic profiles of the 2 
sources of TIL; and in vitro effector function (ability to lyse autologous and 
allogeneic tumor cells) of the 2 sources of TIL.

III.  Evaluate the biologic and immunologic effects of low-dose IFN-G on tumor 
cell surface expression of HLA antigens, expression of cell surface tumor 
antigens (Leu-7, GD2), and peripheral blood mononuclear function.

IV.  Evaluate whether quantitative and/or qualitative changes in tumor cell 
surface expression of HLA antigens alter susceptibility of the tumor cells to 
lysis by autologous TIL, in vitro cytotoxicity of autologous TIL, and in vivo 
response to IL-2/TIL.

V.  Evaluate the pharmacokinetics of intermittent intravenous bolus IL-2 
administration in children.

VI.  Evaluate the toxicity of this regimen with particular reference to 
hemodynamic and renal parameters.

Entry Criteria

Disease Characteristics:

See General Eligibility Criteria

Patient Characteristics:

See General Eligibility Criteria

General Eligibility Criteria:

Patients over 1 to under 21 years of 
age with neuroblastoma who have failed conventional chemotherapy, i.e., with 
progressive disease during initial therapy, residual disease at the completion 
of therapy, or recurrent local or metastatic disease off therapy.  Patients 
must have solid tumor from which TIL can be harvested, and measurable disease 
must exist post-TIL harvest.  Patients with cortical bone lesions or bone 
marrow infiltration as the sole site of disease pre-TIL harvest are excluded; 
those with bone marrow disease as the sole site of measurable disease post-TIL 
harvest are eligible only if urine or serum catecholamine levels are elevated. 
 Parenchymal CNS lesions exclude.  At least 3 weeks must have elapsed since 
prior chemotherapy or radiotherapy, other than limited, palliative irradiation 
of small lesions distant from the solid tumor sites from which TIL will be 
harvested.  A life expectancy of 8 weeks is required, as is adequate 
hematologic, hepatic, and renal function demonstrated as follows:  WBC at 
least 3,000 and platelets at least 100,000 (in the absence of bone marrow 
infiltration by tumor); total bilirubin no greater than 1.5 mg/dl (unless 
further elevation can be ascribed to a benign condition such as Gilbert's 
syndrome) and SGOT/SGPT no greater than 5 x the upper limit of normal for age 
(in the absence of liver metastases); and serum creatinine no greater than 2 x 
the upper limit of normal for age, creatinine clearance at least 40 
ml/min/1.73 sqm BSA, and radionuclide GFR at least 40 ml/min/1.73 sqm BSA.  An 
LVEF greater than 45% on MUGA scan is required, and patients must be free of 
abnormal shortening fraction on echocardiogram and must have no arrhythmias 
requiring medical therapy.  Patients with coagulopathies requiring oral or 
parenteral anticoagulation are ineligible, as are those with bleeding 
disorders (PT or PTT greater than 1.5 x the upper limit of normal) that are 
not the result of a previously diagnosed clotting factor deficiency (e.g., 
Factor VIII deficiency).  Pulmonary dysfunction, manifested by supplemental 
oxygen requirement, pleural effusion, or loss of lung volume of greater than 
25%, excludes.  Patients must be free of active systemic infection, must be 
HbsAg and HIV antibody negative, and must be free of any other congenital or 
acquired immunodeficiency syndrome.  Patients with a history of malignant 
hyperthermia subsequent to inhaled anesthesia are ineligible, as are those who 
require concurrent steroid therapy.  Pregnancy excludes.

Expected Enrollment

14 to 30 patients will be treated with TIL, and an equal number of patients in 
whom TIL cannot be successfully expanded will also be studied.  The study is 
expected to be completed in 24-36 months.

Outline

Nonrandomized study.  Patients are treated sequentially on Regimens A and B.

Regimen A:  Biological Response Modifier Therapy followed by Single-agent 
Chemotherapy with Hematologic Toxicity Attenuation.  Interferon gamma 
(Genentech), IFN-G, NSC-600662; followed by Carboplatin, CBDCA, NSC-241240; or 
Cyclophosphamide, CTX, NSC-26271; with Granulocyte Colony Stimulating Factor 
(Amgen), G-CSF, NSC-614629.

Regimen B:  Biological Response Modifier Therapy.  IFN-G; Interleukin-2 
(Cetus), IL-2, NSC-373364; Tumor Infiltrating Lymphocytes, TIL (expanded in 
vitro with Interleukin-4, IL-4, NSC-620211 and/or IL-2).

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Marc Horowitz, MD, Protocol chair		Ph: 832-822-4215