NeuroblastomaPhase 2NCT00874315
Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed or Refractory High-Risk NBL.
A Phase 2 study testing anti-thymocyte globulin, busulfan and cyclosporine in people with Neuroblastoma, run by Nationwide Children's Hospital at 4 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 1 year to 18 years
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- anti-thymocyte globulin, busulfan and cyclosporine
- Type of treatment
- Injection or infusion, Surgery or procedure
- How many people
- 0 participants
- Where
- 4 sitesUnited States
- Study dates
- Sep 2008to Jun 2012
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
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
Trial locations and contacts
4 sites in 1 country.
United States4 sites
Children's Memorial Hospital
Chicago, Illinois
Nationwide Children's Hospital
Columbus, Ohio, 43205
Children's Hopsital of Wisconsin
Milwaukee, Wisconsin
Morgan Stanley Children's Hospital of NY
New York, New York
About this study
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.
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.
Read the 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
- Being tested
- anti-thymocyte globulin, busulfan, cyclosporine, fludarabine phosphate, mycophenolate mofetil
- Keywords
- recurrent or refractory neuroblastoma
- Medical subject headings
- Neuroblastoma, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
anti-thymocyte globulinOther
Also called Thymoglobulin
2.5 mg/kg/day for 4 doses on day -3, -2 , -1 and day +2.
busulfanDrug
Also called Busulfex
0.8 mg/kg/dose for total of 8 doses.
cyclosporineDrug
Also called Sandimmune, Gengraf, Neoral.
1.5 mg/kg/dose every 12 hours.
Also called Fludara
30 mg/m2/day for 5 days.
Also called Cell-cept
15 mg/kg/dose every 8 hours
tacrolimusDrug
0.03 mg/kg/day as continuous infusion or 12 hour divided doses
allogeneic hematopoietic stem cell transplantationProcedure or surgery
Donor stem cell transplantation from HLA matched sibling donor or an unrelated donor.
What is being measured
The primary outcome is the main question the study is designed to answer.
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
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.
Measured: 100 days post-HSCT
Secondary outcomes (3)
Progression-free survival (PFS) at 1 year
Measured: 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)
Measured: 3 and 6 months post-SCT
Relationship between presence of killer immunoglobulin-like receptor (KIR) mismatches and clinical endpoints
Measured: 3 and 6 months post-HSCT
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2009 (estimated)
- Study startSep 2008
- Primary completionJun 2012
- Study completionJun 2012
Why it stopped: lack of accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- More trials run by Nationwide Children's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nationwide Children's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Sandeep Soni, MD, Principal investigator, Nationwide Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00874315
- Sponsor's protocol ID
- CDR0000636111
- Other IDs
- NCH-08-0234, IRB-2008-0230
- Status last verified
- Oct 2015
- First submitted
- 1 Apr 2009
- Last updated
- 16 Oct 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT00874315
- Acronym / sponsor ID
- CDR0000636111
- Conditions
- Neuroblastoma
- Keywords
- recurrent or refractory neuroblastoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: lack of accrual
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Nationwide Children's HospitalUniversity, hospital or other
- Study start
- Sep 2008
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 2 Apr 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 1 year to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| anti-thymocyte globulinAlso: Thymoglobulin2.5 mg/kg/day for 4 doses on day -3, -2 , -1 and day +2. | Other | – |
| busulfanAlso: Busulfex0.8 mg/kg/dose for total of 8 doses. | Drug | – |
| cyclosporineAlso: Sandimmune, Gengraf, Neoral.1.5 mg/kg/dose every 12 hours. | Drug | – |
| fludarabine phosphateAlso: Fludara30 mg/m2/day for 5 days. | Drug | – |
| mycophenolate mofetilAlso: Cell-cept15 mg/kg/dose every 8 hours | Drug | – |
| tacrolimus0.03 mg/kg/day as continuous infusion or 12 hour divided doses | Drug | – |
| allogeneic hematopoietic stem cell transplantationDonor stem cell transplantation from HLA matched sibling donor or an unrelated donor. | Procedure or surgery | – |
Primary outcome
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.
3 secondary outcomes
Progression-free survival (PFS) at 1 year
Time frame: 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
Relationship between presence of killer immunoglobulin-like receptor (KIR) mismatches and clinical endpoints
Time frame: 3 and 6 months post-HSCT
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sandeep Soni, MD principal investigator
Nationwide Children's Hospital
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing anti-thymocyte globulin, busulfan and cyclosporine in people with Neuroblastoma, run by Nationwide Children's Hospital at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 16 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary 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 (time frame: 100 days post-HSCT). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2015.