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

Primary Purpose

Neuroblastoma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Zoledronic Acid
Aldesleukin
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroblastoma focused on measuring Neuroblastoma, Pediatrics, Refractory, Immunotherapy, Biological therapy, Lymphocytes, Cancer, Bisphosphonate

Eligibility Criteria

2 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham-Children's of Alabama

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Zoledronic Acid and Interleukin-2

Arm Description

Outcomes

Primary Outcome Measures

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.

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
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
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.
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.
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.

Full Information

First Posted
July 13, 2011
Last Updated
December 1, 2014
Sponsor
University of Alabama at Birmingham
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1. Study Identification

Unique Protocol Identification Number
NCT01404702
Brief Title
Pilot Study of Zoledronic Acid and Interleukin-2 for Refractory Pediatric Neuroblastoma
Official Title
Pilot Study of Zoledronic Acid and Interleukin-2 for Refractory Pediatric Neuroblastoma: Assessment of Tolerability and In Vivo Expansion γδ T-Cells
Study Type
Interventional

2. Study Status

Record Verification Date
December 2014
Overall Recruitment Status
Terminated
Why Stopped
Accrual slower than anticipated
Study Start Date
August 2011 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Alabama at Birmingham

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroblastoma
Keywords
Neuroblastoma, Pediatrics, Refractory, Immunotherapy, Biological therapy, Lymphocytes, Cancer, Bisphosphonate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Zoledronic Acid and Interleukin-2
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Zoledronic Acid
Other Intervention Name(s)
Zometa
Intervention Description
4 mg/m2/dose given iv on day 0 of every 28 day cycle
Intervention Type
Biological
Intervention Name(s)
Aldesleukin
Other Intervention Name(s)
Proleukin, Interleukin-2
Intervention Description
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
Primary Outcome Measure Information:
Title
Evaluate the safety and toxicity of zoledronic acid and aldesleukin
Description
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.
Time Frame
1.5 years
Secondary Outcome Measure Information:
Title
Evaluate the biologic function of autologous expanded/activated gamma delta T cells in neuroblastoma patients receiving therapy with zoledronic acid and aldesleukin
Description
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.
Time Frame
3 years
Title
Evaluate immune phenotype of in vivo expanded/activated autologous gamma delta T cells
Description
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.
Time Frame
3 years
Title
To document tumor response in patients with measurable disease.
Description
Tumor response and progression will be assessed and documented utilizing the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Time Frame
3 years
Title
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.
Description
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.
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph Pressey, MD
Organizational Affiliation
The University of Alabama at Birmingham
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham-Children's of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States

12. IPD Sharing Statement

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

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