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Fludarabine, Busulfan, and Antithymocyte Globulin Followed By Donor Stem Cell Transplant in Treating Young Patients With High-Risk Neuroblastoma That Has Relapsed or Not Responded to Treatment
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), March 2009
First Received: April 1, 2009   No Changes Posted
Sponsored by: Nationwide Children's Hospital
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00874315
  Purpose

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, and antithymocyte globulin before a donor stem cell transplant helps stop the growth of tumor cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining tumor cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine, tacrolimus, and mycophenolate mofetil before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine together with busulfan and antithymocyte globulin followed by donor stem cell transplant works in treating young patients with high-risk neuroblastoma that has relapsed or not responded to treatment.


Condition Intervention Phase
Neuroblastoma
Biological: anti-thymocyte globulin
Biological: graft-versus-tumor induction therapy
Drug: busulfan
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Drug: tacrolimus
Genetic: gene expression analysis
Genetic: polymerase chain reaction
Other: enzyme-linked immunosorbent assay
Other: flow cytometry
Other: immunoenzyme technique
Other: laboratory biomarker analysis
Procedure: allogeneic bone marrow transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Phase II

Study Type: Interventional
Study Design: Treatment
Official Title: A Multicenter Pilot Study of Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation With in-Vivo T-Cell Depletion to Evaluate the Role of NK Cells and KIR Mis-Matches in Relapsed or Refractory High-Risk Neuroblastoma.

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Feasibility as measured by the incidence of donor engraftment, transplant-related mortality, and grade III-IV acute graft-vs-host disease (GVHD) at day 100 and the incidence of extensive chronic GVHD within the first year post-transplantation [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression-free survival (PFS) at 1 year [ Designated as safety issue: No ]
  • Relationship between biologic endpoints (e.g., number of natural killer [NK] cells infused, NK cell recovery, and NK cell chimerism status) and clinical endpoints (e.g., donor engraftment, acute GVHD, transplant-related mortality, and PFS) [ Designated as safety issue: No ]
  • Relationship between presence of killer immunoglobulin-like receptor (KIR) mismatches and clinical endpoints [ Designated as safety issue: No ]

Estimated Enrollment: 25
Study Start Date: September 2008
Estimated Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • To determine the feasibility of allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning regimen comprising fludarabine phosphate, busulfan, and anti-thymocyte globulin, in terms of donor engraftment, transplant-related mortality, and development of acute and chronic graft-vs-host disease, in pediatric patients with high-risk relapsed or refractory neuroblastoma.

Secondary

  • To elucidate the role of natural killer (NK) cells as effectors of graft-vs-tumor effect in these patients.
  • To evaluate the role of killer immunoglobulin-like receptor (KIR) mismatches in the donor-recipient pairs on the outcomes of these patients.
  • To determine the incidence of progression-free survival at 1 year post-transplantation in these patients.

OUTLINE: This is a multicenter study.

  • Reduced-intensity conditioning regimen: Patients receive fludarabine phosphate IV over 1 hour on days -10 to

    • 6, busulfan IV over 2 hours once on day -10 and then every 6 hours on days -5 and -4, and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1 and on day 2.
  • Transplantation: Patients undergo allogeneic bone marrow or G-CSF-mobilized peripheral blood stem cell transplantation on day 0.
  • Graft-vs-host disease (GVHD) prophylaxis: Patients receive cyclosporine or tacrolimus IV or orally beginning on day -2 and continuing until day 60 or day 100, followed by a taper until day 100 or day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil IV or orally on days 1-30, followed by a taper until day 60 in the absence of GVHD. Blood samples are collected at baseline and on days 30, 60, and 100 for correlative laboratory studies. Samples are analyzed for killer immunoglobulin-like receptor (KIR) mismatches by genotyping and immunophenotyping methods (PCR and flow cytometry); natural killer (NK) cell reconstitution by flow cytometry; and NK cell function, allo-reactivity, and activity by ELISPOT and ELISA.

After completion of study treatment, patients are followed periodically for 1 year.

  Eligibility

Ages Eligible for Study:   1 Year to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of high-risk neuroblastoma, meeting one of the following criteria:

    • Refractory disease, defined as no response, mixed response, or progressive disease after completion of induction therapy administered according to clinical trials COG-A3973 or COG-ANBL0532 (or other similar high-intensity induction regimen)
    • Relapsed following high-dose chemoradiotherapy including autologous stem cell transplantation
  • Achieved a complete remission (CR), very good partial remission (VGPR), or partial remission (PR) after ≤ 2 different salvage regimens, as defined by the following:

    • In CR after treatment with some form of salvage therapy (e.g., ¹³¹I-MIBG, antibody-based therapy, or any other COG or NANT salvage-therapy regimen)
    • In VGPR or PR after salvage therapy

      • No more than 3 sites of skeletal disease as determined by an ¹²³I-MIBG scan (for regional involvement of the skeleton [e.g., pelvis, spine], the tumor involvement should be < 25% of the site)
      • Bone marrow involvement (< 25% neuroblasts) by morphologic exam within the past 2 weeks
      • Patients with soft tissue disease are eligible provided they exhibit either a VGPR or PR in the primary soft tissue mass and in any sites of metastatic soft tissue disease
  • Disease status meeting one of the following criteria:

    • Minimal residual disease
    • Disease considered responsive to a salvage regimen
    • Stable disease
  • No rapidly progressive disease
  • Donors must meet one of the following criteria:

    • Matched, related donor (6/6 or 5/6) (bone marrow donor allowed)
    • HLA-matched unrelated donor (10/10 match on high-resolution [HR] typing of HLA-A, B, C, DRB1, and DQB1)
    • One allele- or antigen-mismatched unrelated donor (9/10 match on HR typing), mismatched at HLA-C only
    • One allele- or antigen-mismatched unrelated donor (9/10 match on HR typing), mismatched at HLA-A, B, DRB1, or DQB1 (only when HLA-C mismatch is not available)

PATIENT CHARACTERISTICS:

  • Karnofsky/Lansky performance status 60-100%
  • ANC > 500/mm^3
  • Creatinine clearance or radioisotope GFR ≥ 60 mL/min
  • Total bilirubin < 3.0 mg/dL
  • AST or ALT < 5 times upper limit of normal
  • Shortening fraction ≥ 25% by ECHO OR ejection fraction > 30% by MUGA
  • FEV_1 and DLCO ≥ 30% OR normal chest x-ray, pulse oximetry, and venous blood gas
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative
  • No active or recent (within the past 30 days) fungal infection
  • No proven or suspected sepsis, pneumonia, or meningitis unless appropriate therapeutic measures have been initiated to control the infection and systemic signs are no longer life-threatening
  • No requirement for oxygen or ventilator support

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Prior tandem autologous stem cell transplantations (according to clinical trial COG-ANBL0532) allowed
  • No prior allogeneic hematopoietic stem cell transplantation
  • More than 2 months since prior autologous stem cell transplantation, myeloablative therapy, total-body irradiation, whole abdominal radiotherapy, or therapeutic ¹³¹I-MIBG
  • More than 3 weeks since prior chemotherapy, immunotherapy (including anti-GD2 regimen), or biologic response modifiers and recovered
  • More than 2 weeks since prior local radiotherapy to the sites of metastatic disease
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00874315

Locations
United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center Recruiting
Columbus, Ohio, United States, 43210-1240
Contact: Ohio State University Cancer Clinical Trial Matching Service     866-627-7616     osu@emergingmed.com    
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Sandeep Soni, MD     614-722-3582        
Sponsors and Collaborators
Nationwide Children's Hospital
Investigators
Principal Investigator: Sandeep Soni, MD Nationwide Children's Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Nationwide Children's Hospital ( Sandeep Soni )
Study ID Numbers: CDR0000636111, NCH-08-0234, IRB08-00234
Study First Received: April 1, 2009
Last Updated: April 1, 2009
ClinicalTrials.gov Identifier: NCT00874315     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
recurrent neuroblastoma

Study placed in the following topic categories:
Antimetabolites
Anti-Infective Agents
Neuroectodermal Tumors, Primitive
Cyclosporine
Immunologic Factors
Fludarabine monophosphate
Tacrolimus
Immunosuppressive Agents
Cyclosporins
Neuroblastoma
Recurrence
Antilymphocyte Serum
Neuroectodermal Tumors
Antifungal Agents
Neoplasms, Germ Cell and Embryonal
Busulfan
Mycophenolate mofetil
Neuroepithelioma
Antineoplastic Agents, Alkylating
Fludarabine
Antirheumatic Agents
Alkylating Agents
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:
Antimetabolites
Anti-Infective Agents
Antimetabolites, Antineoplastic
Neuroectodermal Tumors, Primitive
Cyclosporine
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Neoplasms, Nerve Tissue
Physiological Effects of Drugs
Tacrolimus
Cyclosporins
Neuroblastoma
Antifungal Agents
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal
Mycophenolate mofetil
Dermatologic Agents
Alkylating Agents
Neoplasms by Histologic Type
Enzyme Inhibitors
Fludarabine monophosphate
Immunosuppressive Agents
Pharmacologic Actions
Antilymphocyte Serum
Neuroectodermal Tumors
Neoplasms
Busulfan
Myeloablative Agonists
Fludarabine

ClinicalTrials.gov processed this record on September 11, 2009