Interleukin-12 (IL-12) and Interleukin-2 are investigational drugs that have been used to treat kidney cancer and melanoma in adults.

The purpose of this study is to determine whether giving IL-12 alone or in combination with Interleukin-2 (IL-2) helps in the treatment of children with neuroblastoma, a malignant tumor that appears to be derived from neural crest cells.

Approximately 30 children and adolescents will participate in this study. Before the drug treatment begins, participants will undergo extensive examinations and testing, including a physical exam, blood work, urinalysis, chest x-ray, pregnancy test (where appropriate), bone marrow tests, various scans, and heart- and lung-function tests. They will receive up to four 28-day cycles of treatment. Each patient will receive doses of either IL-12 alone or IL-12 administered in combination with IL-2. Doctors will monitor participants' progress and look for signs of improvement in each patient's condition (e.g., decrease in tumor size or growth).

Condition	Treatment or Intervention	Phase
Neuroblastoma	Drug: IL-12/IL-2 Combinations	Phase I

The identification of novel approaches to complement existing modalities utilized to treat patients with cancer remains an important and challenging goal. Interest in the use of biological agents has been heightened recently by accumulating preclinical and clinical evidence supporting the use of approaches based on tumor vaccines and/or cytokine combinations delivered either systemically or loco-regionally. Recombinant interleukin-12 (IL-12) is a recently described cytokine, which possesses potent antitumor activity. In animal models, IL-12 has shown significant therapeutic activity both as a tumor vaccine adjuvant and alone or in combination with other cytokines such as interleukin-2 (IL-2). These studies suggest that IL-12 could serve as a useful antitumor agent in humans as well. Although phase I studies of IL-12/IL-2 combinations have been performed in adults, and IL-2 alone has been investigated extensively in children and is approved for use in adult patients with renal cell carcinoma and melanoma, no trials to evaluate the combination of IL-12 and IL-2 in children with malignancy have been performed to date. This phase I dose escalation study will define the maximum tolerated dose and dose-limiting toxicities of IL-12+/-pulse IL-2 and will assess the immunoregulatory and antitumor effects of this combination administered intravenously to children and adolescents with persistent and/or refractory neuroblastoma.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Age
Patients must be greater than or equal to 3 years of age and less than or equal to 21 years of age at tine of study entry.
Diagnostic Criteria:
Patients must have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) verified by histology and/or demonstration of tumor cells in bone marrow with elevated urinary catecholamines.
Disease Status:
Patients are eligible if they have had standard therapy and have been demonstrated to have persistent/refractory or recurrent disease.
Patients with persistent and/or refractory neuroblastoma are eligible if they have at least one of the following:
-Biopsy-proven residual disease greater than or equal to 12 weeks after myeloablative therapy.
-Progressive disease after non-myeloablative therapy.
Patients with recurrent neuroblastoma will be considered eligible based on any of the following:
-Biopsy-proven recurrent soft tissue disease.
-MIBG-positive lesions that also is revealed by any other imaging modality or that is visible by repeat MIBG obtained 2-4 weeks or more apart.
-Bone marrow disease documented by standard histology of bilateral biopsy/aspirate specimens.
-Progressive or stable disease after treatment with at least one prior standard salvage regimen.
Performance Status and Life Expectancy:
Patients must have a performance status of 0 or 1 and a life expectancy of greater than or equal to 12 weeks.
Viral Serology:
Patients must have negative serologic testing for hepatitis A (anti-hepatitis A IgM), B (hepatitis B sAg), and C (anti-HCV) to limit confounding variables in the assessment of the potential hepatic toxicity of this combination. A positive hepatitis B titer does not exclude patient if immunization has been performed and if there is no history of disease.
Patients must have negative serologic testing for human immunodeficiency virus (HIV) given the uncertain impact of rhIL-12 and/or rhIL-2 administration on viral replication, and the potential alterations in immune responsiveness among patients concurrently infected with HIV.
Organ Function:
Patients must have recovered from the toxicity of prior therapy including the following:
Kidney Function: Normal renal function as defined by creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73m(2) or a serum creatinine based on age as follows: less than 5 years: 0.8mg/dl; 5 years to less than or equal to 10 years: 1.0 mg/dl; 10 years to less than or equal to 15 years: 1.2 mg/dl; greater than 15 years: 1.5 mg/dl.
Cardiac Function: Patients must have normal cardiac function documented by ECG AND a normal ejection fraction (greater than or equal to 50%) by echocardiogram or radionuclide MUGA evaluation, OR normal fractional shortening (greater than or equal to 30%) by echocardiogram.
Liver Function: Patients must have adequate liver function defined as AST and ALT less than2.5 x the upper limit of normal and a total serum bilirubin less than 2.0 mg/dl.
Hematopoietic Criteria:
Patients must have adequate hematopoietic function (without growth factor support) as evidenced by:
-Absolute Neutrophil Count (ANC) greater than or equal to 1500 cells/mm(3);
-Platelets greater than or equal to 75,000/mm(3)
Transfusion to achieve this criterion will not be allowed.
Lung Function:
Normal lung function as manifested by no dyspnea at rest or exercise intolerance.
Additional pulmonary assessment should be obtained for patients with clinical symptoms suggestive of pulmonary dysfunction or those with a history of any of the following: history of total body or lung irradiation, reactive airway disease, thoracic or chest wall surgery, or prior treatment with nitrosureas. Pulse oximetry demonstrating an oxygen saturation of 94% or greater will be considered acceptable for protocol enrollment in these patients. In patients greater than or equal to 10 years old, pulmonary function testing should be attempted. Normal pulmonary function testing will be defined by DCLO greater than 60% of predicted and FEV1 greater than 70% of predicted.
Pregnancy Test:
Adolescent females of childbearing potential must have a negative serum or urine beta-HCG pregnancy test within 14 days prior to initiation of study therapy, given the potential impact of this regimen on fetal development and maternal-fetal interactions.
EXCLUSION CRITERIA:
Patients with a history of previous therapy with rhIL-12 will be excluded from study participation.
Systemic corticosteroids, radiotherapy, chemotherapy, or other investigational agents within 4 weeks prior to study entry.
Treatment with any of the following agents with known immunomodulatory effects within 2 weeks prior to study entry:
-G-CSF (filgastrim)/GM-CSF (sarmogastrim)
-Non-corticosteroid hormonal therapy (including oral birth control pills)
-retinoic acid
-fenretinide
-interferons or interleukins
-cytokine-fusion proteins
-growth hormone
-IVIG
All patients with a history of or current intracranial metastatic disease to the brain parenchyma or patients with current skull-based bony disease with space-occupying intracranial extension are not eligible.
Patients with skull-based bony disease without space-occupying intracranial extension are eligible.
Patients with a history of hematologic malignancies including leukemia or lymphoma.
History of allogeneic bone marrow or solid organ transplantation.
History of treatment with myeloablative chemotherapy followed by stem cell transplantation within 12 weeks of study entry.
History of enrollment of Children's Oncology Group (COG) protocol A3973, unless the patient has experienced disease progression or has biopsy proven residual disease greater than or equal to 12 weeks after myeloablative therapy.
Concurrent administrative of any other investigational agent.
Patients with significant intercurrent illnesses (unrelated to cancer or its treatment) and/or any of the following:
-Critically-ill or medically unstable patients
-Patients with active infection or other significant systemic illness
-Presence of clinically significant pleural effusion
-Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance
-History of malignant hyperthermia
-Concurrent or history of autoimmune disease with the following specific exceptions: Patients with a history of isolated autoimmune thyroid disease that has been treated with surgical or radionuclide ablation; Patients with a single isolated episode of acute idiopathic thrombocytopenic purpura (ITP) that has resolved, and never recurred.
History of congenital or acquired coagulation disorder.
Positive direct Coombs testing or history of hemolytic anemia.
Patients with a history of ongoing or intermittent bowel obstruction.
Females who are pregnant or lactating or male or female patients who are not using effective contraception during the treatment period will be excluded in light of recognized adverse effects of both rhIL-12 and rhIL-2 on maternal fetal interactions and fetal development, and the unknown impact of these agents on breast-feeding infants.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  030252; 03-C-0252
Record last reviewed:  June 23, 2004
Last Updated:  June 23, 2004
Record first received:  July 25, 2003
ClinicalTrials.gov Identifier:  NCT00065494
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-18