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

October 14, 2015 updated by: Nationwide Children's Hospital

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.

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.

Study Overview

Status

Withdrawn

Conditions

Neuroblastoma

Intervention / 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.

Study Type

Interventional

Phase

Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Illinois
  - Chicago, Illinois, United States
    - Children's Memorial Hospital
- New York
  - New York, New York, United States
    - Morgan Stanley Children's Hospital of NY
- Ohio
  - Columbus, Ohio, United States, 43205
    - Nationwide Children's Hospital
- Wisconsin
  - Milwaukee, Wisconsin, United States
    - Children's Hopsital of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 18 years (Child, Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	100 days post-HSCT

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival (PFS) at 1 year Time Frame: 1 year post- HSCT	1 year post- HSCT
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	3 and 6 months post-SCT
Relationship between presence of killer immunoglobulin-like receptor (KIR) mismatches and clinical endpoints Time Frame: 3 and 6 months post-HSCT	3 and 6 months post-HSCT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nationwide Children's Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2008

Primary Completion (Actual)

June 1, 2012

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

April 1, 2009

First Submitted That Met QC Criteria