Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed or Refractory High-Risk NBL.

This study has been terminated.
(lack of accrual)
Sponsor:
Information provided by (Responsible Party):
Sandeep Soni, M.D., Nationwide Children's Hospital
ClinicalTrials.gov Identifier:
NCT00874315
First received: April 1, 2009
Last updated: August 12, 2013
Last verified: August 2013
  Purpose

RATIONALE: - Relapsed or refractory Neuroblastoma (NBL) carries a very poor prognosis and children with relapsed NBL have an overall 3 year survival rate of < 10%. Hematopoietic Stem Cell Transplant from a different donor (allogeneic), is a form of adoptive cellular therapy , such that infused donor cells find host tumors as foreign and fight them. After transplant, the donor immune cells (i.e. T cells, NK cells) mediate Graft versus Tumor (GVT) effect and may stop tumor from recurring. Also,reduced intensity transplants lead to minimal toxicity and less risk of mortality in heavily pre-treated NBL patients.

PURPOSE: This phase II trial is studying how well giving a reduced intensity(using Fludarabine, Busulfan and antithymocyte globulin)preparative regimen 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
Other: anti-thymocyte globulin
Drug: busulfan
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Drug: tacrolimus
Procedure: allogeneic hematopoietic stem cell transplantation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: 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 Nationwide Children's Hospital:

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 [ Time Frame: 100 days post-HSCT ] [ Designated as safety issue: Yes ]
    The safety and feasibility of reduced intensity allogeneic HSCT will be established in this population by monitoring the incidence of adverse events- 100 day mortality,incidence of severe acute GVHD and non-engraftment of donor cells.


Secondary Outcome Measures:
  • Progression-free survival (PFS) at 1 year [ Time Frame: 1 year post- HSCT ] [ 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) [ Time Frame: 3 and 6 months post-SCT ] [ Designated as safety issue: No ]
  • Relationship between presence of killer immunoglobulin-like receptor (KIR) mismatches and clinical endpoints [ Time Frame: 3 and 6 months post-HSCT ] [ Designated as safety issue: No ]

Enrollment: 2
Study Start Date: September 2008
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Other: anti-thymocyte globulin
    2.5 mg/kg/day for 4 doses on day -3, -2 , -1 and day +2.
    Other Name: Thymoglobulin
    Drug: busulfan
    0.8 mg/kg/dose for total of 8 doses.
    Other Name: Busulfex
    Drug: cyclosporine
    1.5 mg/kg/dose every 12 hours.
    Other Name: Sandimmune, Gengraf, Neoral.
    Drug: fludarabine phosphate
    30 mg/m2/day for 5 days.
    Other Name: Fludara
    Drug: mycophenolate mofetil
    15 mg/kg/dose every 8 hours
    Other Name: Cell-cept
    Drug: tacrolimus
    0.03 mg/kg/day as continuous infusion or 12 hour divided doses
    Procedure: allogeneic hematopoietic stem cell transplantation
    Donor stem cell transplantation from HLA matched sibling donor or an unrelated donor.
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 (test dose) 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, NK cell allo-reactivity 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
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: NCT00874315

Locations
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States
United States, New York
Morgan Stanley Children's Hospital of NY
New York, New York, United States
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Wisconsin
Children's Hopsital of Wisconsin
Milwaukee, Wisconsin, United States
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: Sandeep Soni, M.D., Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT00874315     History of Changes
Other Study ID Numbers: CDR0000636111, NCH-08-0234, IRB-2008-0230
Study First Received: April 1, 2009
Last Updated: August 12, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Nationwide Children's Hospital:
recurrent or refractory neuroblastoma

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
Antilymphocyte Serum
Busulfan
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Fludarabine monophosphate
Tacrolimus
Fludarabine
Mycophenolic Acid
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists

ClinicalTrials.gov processed this record on July 20, 2014