hu14.18-Interleukin-2 Fusion Protein in Treating Young Patients With Recurrent or Refractory Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Biological therapies such as hu14.18-interleukin-2 fusion protein work in different ways to stimulate the immune system and stop tumor cells from growing. PURPOSE: This phase II trial is studying how well hu14.18-interleukin-2 fusion protein works in treating young patients with recurrent or refractory neuroblastoma.

Detailed Description
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OBJECTIVES: Determine the response rate in children with recurrent or refractory neuroblastoma treated with hu14.18-interleukin-2 (hu14.18-IL2) fusion protein. Determine the adverse events of this drug in these patients. Determine the immunologic activation in patients treated with this drug. Determine the induction of anti-hu14.18-IL2 antibody in patients treated with this drug. Correlate antitumor response with measurements of toxicity, immune activation, and anti-hu14.18-IL2 antibody activity in patients treated with this drug. OUTLINE: This is a multicenter study. Patients are stratified according to measurable/evaluable disease (measurable by standard radiographic criteria vs evaluable by MIBG (meta-iodobenzylguanidine) scanning and/or bone marrow histology vs disease identified and quantified by bone marrow immunohistochemistry). For standard radiographic criteria this study will use the definitions of measurable disease from the Response Evaluation Criteria In Solid Tumors (RECIST) from the National Cancer Institute. Complete Response (CR) - Disappearance of all target lesions. No evidence of tumor at any site (chest, abdomen, liver, bone, bone marrow, nodes, etc). Very Good Partial Response (VGPR) - Greater than 90% decrease of the disease measurement for CT/MRI target lesions, taking as reference the disease measurement done to confirm measurable disease in target lesions at study entry; all pre-existing bone lesions with CR by MIBG; MIBG scan can be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Partial Response (PR) - At least a 30% decrease in the disease measurement for CT/MRI target lesions, taking as reference the disease measurement done to confirm measurable disease in target lesions at study entry. Progressive Disease (PD) - Any one of the following: a) At least a 20% increase in the disease measurement for CT/MRI target lesions, taking as reference the smallest disease measurement recorded since the start of treatment. b) Appearance of one or more new lesions or new sites of tumor. c) PD as defined above for either bone marrow or MIBG lesions. Stable disease (SD) - The patient will be classified as stable disease for overall response if there is stable disease by either CT/MRI lesion, bone marrow, or MIBG criteria. No new lesions; no new sites of disease. Patients will be enrolled in 3 strata, and evaluated for antitumor response following 2 monthly courses (treatment on Days 1-3, followed by 25 days of observation,). Patients with progressive disease will be taken off protocol therapy. Patients with stabilization or regression of disease will be eligible to receive 2 more monthly courses of treatment. Additional treatment following course 4 will be allowed for patients showing a continued clinical response, up to a maximum of 10 courses of treatment. Patients are followed for survival. PROJECTED ACCRUAL: A total of 40-60 patients (20 for strata 1 and 2 and 0-20 for stratum 3) will be accrued for this study within 2 years.

Official Title
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A Phase II Study Of hu14.18-IL2 In Children With Recurrent Or Refractory Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: hu14.18-Interleukin-2 fusion protein


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed neuroblastoma Relapsed or refractory to conventional therapy Measurable or evaluable disease documented by 1 of the following criteria: Clinical Radiographic Histologic MIBG (meta-iodobenzylguanidine) scanning Immunocytochemistry No symptomatic pleural effusions or ascites requiring constant or intermittent drainage No clinical or radiological evidence of central nervous system (CNS) disease PATIENT CHARACTERISTICS: Age 21 and under Performance status Karnofsky 50-100% (> 16 years of age) Lansky 50-100% (≤ 16 years of age) Life expectancy At least 8 weeks Hematopoietic Absolute neutrophil count > 1,000/mm^3 Platelet count ≥ 75,000/mm^3* Must not be refractory to platelet transfusions Hemoglobin ≥ 9.0 g/dL* NOTE: *Transfusion allowed if patient is known to have a history of bone marrow involvement with tumor Hepatic Alanine transaminase (ALT) < 2.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Hepatitis B surface antigen negative Renal Creatinine adjusted according to age as follows: No greater than 0.4 mg/dL (≤ 5 months) No greater than 0.5 mg/dL (6 months -11 months) No greater than 0.6 mg/dL (1 year-23 months) No greater than 0.8 mg/dL (2 years-5 years) No greater than 1.0 mg/dL (6 years-9 years) No greater than 1.2 mg/dL (10 years-12 years) No greater than 1.4 mg/dL (13 years and over [female]) No greater than 1.5 mg/dL (13 years to 15 years [male]) No greater than 1.7 mg/dL (16 years and over [male]) OR Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Cardiovascular Shortening fraction ≥ 27% by echocardiogram OR Ejection fraction ≥ 50% by Multi Gated Acquisition Scan (MUGA) No symptomatic congestive heart failure No uncontrolled cardiac rhythm disturbance Pulmonary Pulse oximetry > 94% on room air Forced vital capacity (FVC) > 80% Forced expiratory volume (FEV_1) > 80% No abnormal respiratory function No dyspnea at rest No exercise intolerance No prior history of ventilator support related to lung injury (e.g., pneumonia, hemorrhagic pneumonitis, or capillary leakage) Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative No active uncontrolled infection No active uncontrolled peptic ulcer No objective peripheral neuropathy ≥ grade 2 No significant psychiatric disabilities No seizure disorders requiring antiseizure medications No other concurrent significant illness PRIOR CONCURRENT THERAPY: Biologic therapy Recovered from prior immunotherapy Prior in vivo monoclonal antibodies for biologic therapy or tumor imaging allowed provided there is documented absence of detectable antibody to hu14.18 by serology More than 28 days since prior autologous stem cell transplantation Prior autologous marrow or stem cell infusion using monoclonal antibody-purged specimens allowed More than 1 week since prior growth factors At least 7 days since prior nonmyelosuppressive biologic agents No prior allogeneic bone marrow or stem cell transplantation No concurrent immunomodulating agents No concurrent growth factors Chemotherapy More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered No concurrent anticancer chemotherapy Endocrine therapy No concurrent corticosteroids except 100 mg or less of hydrocortisone (or equivalent) as premedication for blood transfusion or treatment for transfusion reaction No other use of systemic steroids Radiotherapy Recovered from prior radiotherapy At least 2 weeks since prior local palliative radiotherapy (small port) At least 6 months since prior craniospinal radiotherapy At least 6 months since prior total body irradiation At least 6 months since prior radiotherapy to ≥ 50% of the pelvis At least 6 weeks since other prior substantial bone marrow radiotherapy Concurrent radiotherapy to localized painful lesions allowed provided at least 1 measurable or evaluable lesion is not irradiated Surgery More than 2 weeks since prior major surgery (e.g., laparotomy or thoracotomy) No prior organ allografts Other No concurrent immunosuppressive drugs No other concurrent myelosuppressive antineoplastic 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disease Measurable by Standard Criteria(hu14.18-interleukin-2)<br>Patients with residual/refractory neuroblastoma and readily measurable residual/refractory disease using standard radiographic criteria. Standard radiographic criteria for CT/MRI Lesions will use the definitions of measurable disease from the Response Evaluation Criteria In Solid Tumors (RECIST) from the National Cancer Institute. hu14.18-Interleukin-2 fusion protein : Given IV | Biological: hu14.18-Interleukin-2 fusion protein<br>* Given IV<br>* Other names: BB-IND-9798;|
| Experimental: Disease Eval by MIBG or BM Histology (hu14.18-interleukin-2)<br>Patients with residual/refractory neuroblastoma with disease that is not measurable by standard radiographic criteria, but is evaluable by meta-iodobenzylguanidine (MIBG) scanning and/or by bone marrow (BM) histology. hu14.18-Interleukin-2 fusion protein : Given IV | Biological: hu14.18-Interleukin-2 fusion protein<br>* Given IV<br>* Other names: BB-IND-9798;|
| Experimental: Disease Identified by BM Immunohistochemistry Only<br>Patients with residual/refractory neuroblastoma that do not have disease that is measurable by standard radiographic techniques or evaluable by meta-iodobenzylguanidine (MIBG) scanning or bone marrow (BM) histology, however, disease is identified and quantified by BM immunohistochemistry (>5 neuroblastoma cells per 1,000,000 nucleated marrow cells). hu14.18-Interleukin-2 fusion protein : Given IV | Biological: hu14.18-Interleukin-2 fusion protein<br>* Given IV<br>* Other names: BB-IND-9798;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Responders (Response Rate) | Response rate to hu14.18-Interleukin-2 in 3 separate strata of patients with recurrent or refractory neuroblastoma. Patients will have radiologic (CT/MRI) tumor and urine homovanillic acid (HVA)/vanillylmandelic acid (VMA) measurements. Patients with prior marrow involvement will have marrow assessments. Patients with MIBG+ (iodine-131-meta-iodobenzylguanidine) prior disease will have MIBG scans performed. For CT/MRI lesions, measureable disease is measured by the Response Evaluation Criteria In Solid Tumors (RECIST) from the National Cancer Institute. RECIST (v1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions. | Up to 30 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent neuroblastoma