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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.


Phase 2
1 Year
18 Years
Not Enrolling
Both
Neuroblastoma

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Trial Information

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.


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

100 days post-HSCT

Safety Issue:

Yes

Principal Investigator

Sandeep Soni, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Nationwide Children's Hospital

Authority:

United States: Institutional Review Board

Study ID:

CDR0000636111

NCT ID:

NCT00874315

Start Date:

September 2008

Completion Date:

June 2012

Related Keywords:

  • Neuroblastoma
  • recurrent or refractory neuroblastoma
  • Neuroblastoma

Name

Location

Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Memorial HospitalChicago, Illinois  60614
Morgan Stanley Children's Hospital of NYNew York, New York  
Children's Hopsital of WisconsinMilwaukee, Wisconsin