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

NCT ID: NCT00874315

Last Updated: 2015-10-16

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-09-30
• Study Completion Date: 2012-06-30

Brief Summary

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.

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.

Conditions

Neuroblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

anti-thymocyte globulin

2.5 mg/kg/day for 4 doses on day -3, -2 , -1 and day +2.

Intervention Type: OTHER

busulfan

0.8 mg/kg/dose for total of 8 doses.

Intervention Type: DRUG

cyclosporine

1.5 mg/kg/dose every 12 hours.

Intervention Type: DRUG

fludarabine phosphate

30 mg/m2/day for 5 days.

Intervention Type: DRUG

mycophenolate mofetil

15 mg/kg/dose every 8 hours

Intervention Type: DRUG

tacrolimus

0.03 mg/kg/day as continuous infusion or 12 hour divided doses

Intervention Type: DRUG

allogeneic hematopoietic stem cell transplantation

Donor stem cell transplantation from HLA matched sibling donor or an unrelated donor.

Intervention Type: PROCEDURE

Other Intervention Names

Thymoglobulin; Busulfex; Sandimmune, Gengraf, Neoral.; Fludara; Cell-cept

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Nationwide Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sandeep Soni, MD

Role: PRINCIPAL_INVESTIGATOR

Nationwide Children's Hospital

Locations

Children's Memorial Hospital

Chicago, Illinois, United States

Morgan Stanley Children's Hospital of NY

New York, New York, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Children's Hopsital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

Other Identifiers

NCH-08-0234

Identifier Type: REGISTRY

Identifier Source: secondary_id

IRB-2008-0230

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000636111

Identifier Type: -

Identifier Source: org_study_id