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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


Phase 1
18 Months
17 Years
Open (Enrolling)
Both
Neuroblastoma

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

15 years

Safety Issue:

Yes

Principal Investigator

Doug Myers, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Mercy Hospital

Authority:

United States: Food and Drug Administration

Study ID:

STALLONe

NCT ID:

NCT01460901

Start Date:

October 2011

Completion Date:

October 2028

Related Keywords:

  • Neuroblastoma
  • Neuroblastoma
  • Relapsed
  • Refractory
  • Neuroblastoma

Name

Location

Children's Mercy HospitalKansas City, Missouri  64108