Pilot Study of Zoledronic Acid and Interleukin-2 for Refractory Pediatric Neuroblastoma

Study Overview
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Brief Summary
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Neuroblastoma (NB) is the most common extracranial solid tumor in children, with an annual incidence of 10.5 per million children less than 15 years of age. NB accounts for 15% of childhood cancer deaths. High risk (HR) patients carry a poor prognosis despite treatment with intensive chemotherapy, surgery and/or radiation, autologous bone marrow transplant, and treatment with cis-retinoic acid. New therapies are desperately needed for such patients. Recently, it has been demonstrated that HR NB patients benefit from anti-GD2 antibody therapy which directs the immune system against NB cells. To further explore means of harnessing the immune system to attack NB, the investigators are studying the combination of zoledronic acid (ZOL) and interleukin-2 (IL-2). ZOL has been demonstrated to have direct anti-neuroblastoma effects in laboratory studies. ZOL also augments the production of tumor killing white blood cells called gamma-delta T cells. When used in combination with IL-2, ZOL is capable of eliciting potent anti-cancer effects in patients, in part, via the expansion of gamma-delta T cells. In this present trial the investigators aim to study the tolerability of the combination of ZOL and IL-2 in pediatric NB patients. Patients will also be monitored radiologically for tumor response to therapy. Correlative biological studies will study the ability of this drug combination to elicit the production of NB killing gamma-delta T cells in children.

Official Title
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Pilot Study of Zoledronic Acid and Interleukin-2 for Refractory Pediatric Neuroblastoma: Assessment of Tolerability and In Vivo Expansion γδ T-Cells

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: Zoledronic Acid
* Biological: Aldesleukin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must be diagnosed with treatment-refractory neuroblastoma with no known curative treatment options. Tumor histology should be verified at diagnosis or relapse. Prior to enrollment, a determination of residual disease must be performed Patients must have a Lansky or Karnofsky performance scale score of ≥ 50%. Patients must have a life expectancy of ≥ 2 months (8 weeks). Total absolute neutrophil count (ANC) is at least 750, Hgb≥8 grams/dl, and plts ≥ 75K. PRBC transfusions are allowed. Patients with bone marrow disease will not evaluable for hematologic toxicity. These patients must have a peripheral absolute neutrophil count 750, platelet count ≥ 50K and Hgb ≥8 grams/dl. Transfusions are permitted to meet both the platelet and hemoglobin criteria. Creatinine clearance or radioisotope GFR > 70mL/min/1.73 m2 or a serum creatinine based on age/gender as follows: ≤ 0.8 mg/dL (for patients 2 to 5 years of age) ≤ 1.0 mg/dL (for patients 6 to 9 years of age) ≤ 1.2 mg/dL (for patients 10 to 12 years of age) ≤ 1.4 mg/dL (for female patients ≥ 13 years of age) ≤ 1.5 mg/dL (for male patients 13 to 15 years of age) ≤ 1.6 mg/dL (for male patients ≥ 16 years of age) Total bilirubin ≤ 2.5 x upper limit of normal (ULN) for age, and SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. SOS (sinusoidal obstruction syndrome, formerly known as veno-occlusive disease [VOD]), if present, should be stable or improving. Shortening fraction of > 27% by echocardiogram, or ejection fraction of > 55% by radionuclide angiography. No evidence of dyspnea at rest. If PFTs are performed, FEV1/FVC > 60% by pulmonary function test. Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled. CNS toxicity < Grade 2. Exclusion Criteria: Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding. All patients and/or their parents or legal guardians must sign a written informed consent. All institutional requirements for human studies must be met. Previous treatment with anti-GD2 and interleukin2 therapy

Ages Eligible for Study
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Minimum Age: 2 Years
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: Zoledronic Acid and Interleukin-2<br> | Drug: Zoledronic Acid<br>* 4 mg/m2/dose given iv on day 0 of every 28 day cycle<br>* Other names: Zometa;Biological: Aldesleukin<br>* Dose Level 1: 3 x 10^6 IU/m2/day given subcutaneously on days 0 through 4 and 14 through 18 every 28 day cycle Dose Level 2: 6 x 10^6 IU/m2/day given subcutaneously on days 0 through 4 and 14 through 18 every 28 day cycle<br>* Other names: Interleukin-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and toxicity of zoledronic acid and aldesleukin | The NCI Common Terminology Criteria for AEs will be used for reporting & identification of dose limiting toxicities. DLTs will include any grade 3 non-hematologic toxicity not included here: Gr 3 nausea & vomiting & diarrhea, Gr 3 fever, Gr 3 skin toxicity that remains stable & tolerable, or improves with treatment within 24 hrs, Gr 3 neurotoxicity with subjective findings, Gr 4 hematologic toxicity, which improves to at least Gr 2 or baseline pre-therapy values within one week of completing IL2 infusion, Gr 3 performance that returns to 50 or higher before the start of the next therapy cycle. | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the biologic function of autologous expanded/activated gamma delta T cells in neuroblastoma patients receiving therapy with zoledronic acid and aldesleukin | The ability of gamma-delta T cells derived from patients' peripheral blood to kill NB cells in vitro will be quantified by standard tumor cytotoxicity assays. | 3 years | 
| Evaluate immune phenotype of in vivo expanded/activated autologous gamma delta T cells | Peripheral blood mononuclear cells will be immunophenotyped by standard conjugation of fluorescent monoclonal antibodies in order to quantify and phenotype patient lymphocytes using flow cytometry. | 3 years | 
| To document tumor response in patients with measurable disease. | Tumor response and progression will be assessed and documented utilizing the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | 3 years | 
| Determine the ability of in vivo expanded/activated gamma delta T cells to infiltrate neuroblastoma tissue using immunohistochemical techniques when post-therapy specimens are available. | Patients with known or suspected bone marrow metastasis will undergo bilateral bone marrow biopsies at the beginning and end of the first course of therapy. This tissue will be fixed and processed per protocol (Appendix I) and infiltrating lymphocytes per hpf will be documented under standard microscopy. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroblastoma, Pediatrics, Refractory, Immunotherapy, Biological therapy, Lymphocytes, Cancer, Bisphosphonate