Biological Therapy in Treating Children With Refractory or Recurrent Neuroblastoma or Other Tumors

Study Overview
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Brief Summary
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RATIONALE: Biological therapies such as hu14.18-interleukin-2 fusion protein use different ways to stimulate the immune system and stop cancer cells from growing. PURPOSE: Phase I trial to study the effectiveness of hu14.18-interleukin-2 fusion protein in treating children who have refractory or recurrent neuroblastoma or other tumors.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of hu14.18-interleukin-2 fusion protein in children with refractory or recurrent neuroblastoma or other GD2-positive tumors. Determine the toxicity and pharmacokinetics of the fusion protein in these patients. Determine the effect of the fusion protein on systemic immune modulation in these patients. Quantitate the antifusion protein antibodies in patients treated with fusion protein. Evaluate antitumor responses resulting from this fusion protein regimen in these patients. OUTLINE: This is a dose-escalation study. Patients receive hu14.18-interleukin-2 (hu14.18-IL2) fusion protein IV over 4 hours once daily on days 1-3. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of hu14.18-IL2 fusion protein until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed every 2 months for 1 year, every 6 months for 3 years, and then annually for 5 years. PROJECTED ACCRUAL: A total of 18-24 patients will be accrued for this study within 1 year.

Official Title
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A Phase I/IB Intergroup Trial of the HU14.18-IL2 Fusion Protein in Children With Refractory Neuroblastoma and Other GD2 Positive Tumors

Conditions
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Melanoma (Skin), Neuroblastoma, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Biological: hu14.18-IL2 fusion protein


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed neuroblastoma or melanoma at original diagnosis Refractory to chemotherapy or recurrence after prior multiagent chemotherapy Measurable or evaluable (detectable by bone scan) metastatic disease OR No evidence of disease if complete response to prior surgical resection, radiotherapy, and/or chemotherapy OR Histologically confirmed tumor expressing GD2 antigen at original diagnosis or relapse Refractory to standard treatment Measurable or evaluable disease by clinical assessments or laboratory markers OR No evidence of disease after prior surgical resection of metastatic, recurrent disease Histologically confirmed recurrent osteogenic sarcoma after prior chemotherapy allowed Soft tissue sarcoma allowed No primary CNS tumors Prior CNS metastases allowed, provided: Disease previously treated Disease clinically stable for 4 weeks before study At least 4 weeks since prior steroids for CNS metastases No clinically detectable pleural effusions or ascites PATIENT CHARACTERISTICS: Age: 21 and under Performance status: Karnofsky 60-100% for children over age 10 Lansky 60-100% for children age 10 and under Life expectancy: At least 12 weeks Hematopoietic: Absolute neutrophil count greater than 1,000/mm^3 Platelet count at least 75,000/mm^3 (transfusion allowed) Hemoglobin at least 9.0 g/dL (transfusion allowed) Hepatic: Bilirubin less than 1.5 mg/dL ALT or AST no greater than 2.5 times normal Hepatitis B surface antigen negative Renal: Creatinine no greater than 1.5 mg/dL OR Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min Cardiovascular: Shortening fraction at least 27% by echocardiogram OR Ejection fraction more than 50% by MUGA scan No congestive heart failure No uncontrolled cardiac rhythm disturbance Pulmonary: FEV_1 and FVC more than 60% of predicted OR No dyspnea at rest No exercise intolerance Oxygen saturation more than 94% by pulse oximetry on room air Neurologic: No seizure disorders requiring antiseizure medications No significant neurologic deficit or grade 2 or greater objective peripheral neuropathy Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative No significant concurrent illnesses unrelated to cancer or its treatment No significant psychiatric disabilities No uncontrolled active infections No uncontrolled active peptic ulcer PRIOR CONCURRENT THERAPY: Biologic therapy: At least 1 week since prior growth factors At least 1 week since prior immunomodulatory therapy Prior monoclonal antibodies allowed if no detectable antibody to hu14.18 Prior autologous bone marrow transplantation (BMT) or stem cell transplantation (SCT) allowed Prior autologous BMT or SCT with monoclonal antibody-purged specimens allowed No concurrent growth factors No concurrent interferon Chemotherapy: See Disease Characteristics At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or melphalan) No concurrent palliative chemotherapy Endocrine therapy: See Disease Characteristics At least 2 weeks since prior glucocorticoids, except for life-threatening symptoms No concurrent corticosteroids No concurrent glucocorticoids, except for life-threatening symptoms Radiotherapy: See Disease Characteristics At least 3 weeks since prior radiotherapy No concurrent palliative radiotherapy Surgery: See Disease Characteristics At least 2 weeks since prior major surgery (e.g., laparotomy or thoracotomy) No prior organ allografts No concurrent palliative surgery Other: Recovered from prior therapy At least 1 week since prior tretinoin At least 3 weeks since prior immunosuppressive therapy No other concurrent immunosuppressive drugs

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DG2 positive relapsed or refractory solid tumors<br>The initial hu14.18-IL2 fusion protein (FP) dose will be 2 mg/m2 given intravenously over 4 hours, daily for 3 days. Five separate dose levels are scheduled: 2 mg/m²/dose (IV over 4 hours) x 3 days, 4 mg/m²/dose (IV over 4 hours) x 3 days, 6 mg/m²/dose (IV over 4 hours) x 3 days, 8 mg/m²/dose (IV over 4 hours) x 3 days, 10 mg/m²/dose (IV over 4 hours) x 3 days. | Biological: hu14.18-IL2 fusion protein<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the MTD and pharmacokinetics of hu14.18-IL2 fusion protein | Determine the MTD of hu14.18-IL2 fusion protein and determine the pharmacokinetics of the fusion protein when given as I.V. injections |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess immunological changes associated with fusion protein therapy |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic osteosarcoma, recurrent neuroblastoma, recurrent osteosarcoma, recurrent melanoma, unspecified childhood solid tumor, protocol specific, metastatic childhood soft tissue sarcoma, recurrent childhood soft tissue sarcoma