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Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma (STALLONe)

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ClinicalTrials.gov Identifier: NCT01460901
Recruitment Status : Completed
First Posted : October 27, 2011
Last Update Posted : February 6, 2015
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Children's Mercy Hospital Kansas City

Brief Summary:
This is a single-center, investigator-initiated, single-arm, pilot study of post-allogeneic transplant, adoptive immunotherapy for the treatment of patients with relapsed/refractory neuroblastoma expressing the mesenchymal tumor marker GD2. Three patients will be treated. The study will focus on the safety and efficacy of allogeneic, donor derived viral specific cytotoxic T-lymphocytes, retrovirally transduced to express a chimeric antigen receptor specific for disialoganglioside, GD2, expressed on neuroblastoma.

Condition or disease Intervention/treatment Phase
Neuroblastoma Biological: Tri-virus specific cytotoxic t-cells Phase 1

Detailed Description:
Neuroblastoma (NB) is the most common extracranial tumor of childhood and prognosis for patients with relapsed or refractory disease is < 10% and there is no standard therapy for these patients. Research toward immunotherapeutic agents has intensified as monoclonal antibody targeting GD2, when incorporated into upfront NB therapy, prolongs survival. Allogeneic Hematopoietic stem cell transplantation (HSCT) has been utilized in patients with NB with evidence of a graft versus tumor (GVT) effect but transplant related mortality (TRM) has nullified the survival benefit. In an effort to harness the GVT effect of allogeneic transplant and lower TRM, harvested viral specific cytotoxic T-cells from the donor will be infused early post-HSCT to the HSCT recipient to shorten the recovery of immunity toward the most significant viral infections. The investigators will also retrovirally transduce the viral specific CTL with a chimeric antigen receptor (CAR) gene complex such that the tV-CTL can expand, via their native T-cell receptors in response to viral infections post-HSCT and carry the capability of killing tumor cells through their transduced receptor which, on the extracellular component of the CAR, has specificity for GD2 expressed on the surface of NB. In essence, the investigators intend to take the specificity of the monoclonal antibody to GD2, already utilized in therapy for NB, and combine this specificity with the cytotoxicity of T-cells to target NB. The investigators hypothesize that the infusion will be safe and viral specificity of the tV-CTL will provide long term immunity to both viral infections and the investigators will see anti-tumor effects.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Donor Derived,Gene Modified, Multi-virus-specific, Cytotoxic T-Lymphocytes Redirected to the Tumor Marker GD2 for Relapsed/Refractory Neuroblastoma Post-allogeneic Stem Cell Transplantation With a Submyeloblative Conditioning Regimen
Study Start Date : October 2011
Actual Primary Completion Date : January 2015
Actual Study Completion Date : January 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma


Intervention Details:
  • Biological: Tri-virus specific cytotoxic t-cells
    Infusion of donor derived tri-virus specific cytotoxic t-cell post allogeneic stem cell transplantation


Primary Outcome Measures :
  1. Infusional and long term safety and persistence of tumor redirected, genetically modified, donor derived, allogeneic multi-virus specific cytotoxic T-cells (tV-CTL) after allogeneic hematopoietic stem cell transplant in patients with neuroblastoma [ Time Frame: 15 years ]
    Immediate and short term toxicity of infusion will be assessed over 8 weeks. Yearly monitoring for insertional mutagenesis/oncogenesis will be performed for 15 years.

  2. Evaluating the survival, expansion, anti-viral and anti-tumor function of infused tV-CTL after allogeneic transplant in patients with neuroblastoma [ Time Frame: 1 year, then yearly for 15 years ]
    Specimens evaluating survival and expansion will be measured weekly for 8 weeks then at 3, 6, 9 & 12 months, then yearly for 15 years. Viral infections will be monitored and tumor evaluated pre and post-cell infusion and as indicated clinically.


Secondary Outcome Measures :
  1. Comparing the frequency and expansion of allogeneic, tumor redirected, multi-virus cytotoxic T-cells to that of identically transduced, autologous EBV-specific T-cells infused in prior studies. [ Time Frame: 1 year then yearly for 15 years ]
    Specimens evaluating survival and expansion will be measured weekly for 8 weeks then at 3, 6, 9 & 12 months, then yearly for 15 years. Viral infections will be monitored and tumor evaluated pre and post-cell infusion and as indicated clinically.

  2. Comparing anti-viral immunity after infusion of gene modified, multi-virus specific T-cells to that of patients receiving viral-specific T-cells without gene modification following allogeneic transplant [ Time Frame: 1 year ]
    Results of PCR for the gene construct and viral infections over the first year as per primary outcome #2 will be compared to trials of viral specific T-cell infusions in patients following allogeneic transplant on other trials.



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Ages Eligible for Study:   18 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Allogeneic transduced tV-CTLs with >15% expression of 14g2a.zeta chimeric antigen receptor
  • Patient or responsible person must be able to understand and sign a permission/assent or consent form for infusion
  • Age 18 months through 17 years at time of relapse/progression
  • Life expectancy >8weeks
  • Karnofsky score 60% or greater if 10 yrs old or older. Lansky score 60% or greater if under 10 yrs old
  • Patient must be HIV negative
  • ANC >500
  • Pulse ox>90% on room air
  • AST/ALT/direct bili <5x upper limit of normal
  • Recovered from toxic effects of all prior chemotherapy
  • Absence of human/anti-mouse antibody (HAMA) (patients who have received prior therapy with murine antibodies)
  • >50% donor engraftment

Exclusion Criteria:

  • Patient pregnant or lactating or refuses birth control methods
  • HIV positive
  • Uncontrolled intercurrent infection
  • Renal failure (creatinine clearance <40ml/min/1.73m2)
  • Active hepatitis or cirrhosis with bilirubin, AST, ALT >5xnormal
  • Rapidly progressive disease
  • Currently receiving any investigational drugs
  • Tumor potentially causing airway obstruction
  • Cardiomegaly or bilateral pulmonary infiltrates on CXR
  • Receiving >0.25mg/kg/day methylprednisolone or equivalent systemic steroid. Topical steroid therapy is acceptable
  • Receiving more than one lymphocyte inhibiting agent (ex. Tacrolimus/CSA and MMF or other similar agent
  • Patients relapsing or progressing before the age of 18 months from Stage I/II disease, and/or those who, in the opinion of their oncologist, may benefit from further conventional therapy
  • Donor lymphocyte infusion in last 28 days
  • Evidence of GvHD greater than or equal to grade 2

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01460901


Locations
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United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
Sponsors and Collaborators
Children's Mercy Hospital Kansas City
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Doug Myers, MD Children's Mercy Hospital Kansas City

Additional Information:
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Responsible Party: Children's Mercy Hospital Kansas City
ClinicalTrials.gov Identifier: NCT01460901     History of Changes
Other Study ID Numbers: STALLONe
00038 ( Other Identifier: NHLBI )
First Posted: October 27, 2011    Key Record Dates
Last Update Posted: February 6, 2015
Last Verified: February 2015

Keywords provided by Children's Mercy Hospital Kansas City:
Neuroblastoma
Relapsed
Refractory

Additional relevant MeSH terms:
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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