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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Alabama at Birmingham
Sponsor:
Information provided by (Responsible Party):
University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT01404702
First received: July 13, 2011
Last updated: May 9, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Neuroblastoma
Drug: Zoledronic Acid
Biological: Aldesleukin
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.

  • uoEvaluate 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.


Estimated Enrollment: 6
Study Start Date: August 2011
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: Zometa
Biological: 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

Other Names:
  • Proleukin
  • Interleukin-2

  Eligibility

Ages Eligible for Study:   2 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01404702

Contacts
Contact: Joseph Pressey, MD 205-638-9285 jpressey@uab.edu
Contact: Julia Adams, RN 205-638-2984 jadams@peds.uab.edu

Locations
United States, Alabama
University of Alabama at Birmingham-Children's of Alabama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Joseph Pressey, MD    205-638-9285    jpressey@uab.edu   
Principal Investigator: Joseph Pressey, MD         
Sub-Investigator: Lawrence Lamb, PhD         
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
Principal Investigator: Joseph Pressey, MD The University of Alabama at Birmingham
  More Information

No publications provided

Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT01404702     History of Changes
Other Study ID Numbers: UAB 1051, F101013003
Study First Received: July 13, 2011
Last Updated: May 9, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of Alabama at Birmingham:
Neuroblastoma
Pediatrics
Refractory
Immunotherapy
Biological therapy
Lymphocytes
Cancer
Bisphosphonate

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Aldesleukin
Interleukin-2
Zoledronic acid
Diphosphonates
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on August 27, 2014