Pilot Study of Zoledronic Acid and Interleukin-2 for Refractory Pediatric Neuroblastoma
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.
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Study of Zoledronic Acid and Interleukin-2 for Refractory Pediatric Neuroblastoma: Assessment of Tolerability and In Vivo Expansion γδ T-Cells|
- Evaluate the safety and toxicity of zoledronic acid and aldesleukin [ Time Frame: 1.5 years ] [ Designated as safety issue: Yes ]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.
- Evaluate the biologic function of autologous expanded/activated gamma delta T cells in neuroblastoma patients receiving therapy with zoledronic acid and aldesleukin [ Time Frame: 3 years ] [ Designated as safety issue: No ]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.
- Evaluate immune phenotype of in vivo expanded/activated autologous gamma delta T cells [ Time Frame: 3 years ] [ Designated as safety issue: No ]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.
- To document tumor response in patients with measurable disease. [ Time Frame: 3 years ] [ Designated as safety issue: No ]Tumor response and progression will be assessed and documented utilizing the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- 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. [ Time Frame: 3 years ] [ Designated as safety issue: No ]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.
|Study Start Date:||August 2011|
|Study Completion Date:||August 2014|
|Primary Completion Date:||August 2014 (Final data collection date for primary outcome measure)|
|Experimental: Zoledronic Acid and Interleukin-2||
Drug: Zoledronic Acid
4 mg/m2/dose given iv on day 0 of every 28 day cycle
Other Name: ZometaBiological: Aldesleukin
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01404702
|United States, Alabama|
|University of Alabama at Birmingham-Children's of Alabama|
|Birmingham, Alabama, United States, 35233|
|Principal Investigator:||Joseph Pressey, MD||The University of Alabama at Birmingham|