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

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

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.

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.

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