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

Primary Purpose

Neuroblastoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
GD2 CAR modified Tri-virus specific cytotoxic t-cells
Sponsored by
Children's Mercy Hospital Kansas City
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroblastoma focused on measuring Neuroblastoma, Relapsed, Refractory

Eligibility Criteria

18 Months - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Mercy Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

GD2 CAR modified Tri-virus CTL infusion

Arm Description

A single infusion of 2x10e6 cells per meter squared was performed 30 to 120 days following allogeneic stem cell transplant.

Outcomes

Primary Outcome Measures

Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks
Immediate: Patients were monitored following infusion to assess for toxicity related to infusion. Potential toxicities related to cellular therapy infusions, such as allergic reaction to the cellular product or cryopreservation media, hemolytic reactions, volume overload, and hemodynamic instability, were monitored. Short Term: Patients were monitored for 8 weeks for short term toxicity related to infusion. Such adverse reactions monitored were acute graft versus host disease and cytokine release syndrome.
Peak Transgene Copy Number Per 1000ng PBMC DNA
Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.
Death Within 8 Weeks of Infusion

Secondary Outcome Measures

Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well
The following analyses were performed on peripheral blood samples from patients at protocol assigned time points (pre-infusion, post-infusion at 4 hrs, weeks 1,2,4,6 and 8, month 3, 6 and 12: ELISPOT assay for CMV, Adenovirus and EBV specific CTL reported as SFU (spot forming unit) per 2x10e5 mononuclear cells
Maximum Tumor Response (RECIST 1.1)
Pre and post-therapy evaluation by modalities consistent with prior disease evaluation in each patient. When possible, tumors were assessed per Response Evaluation Criteria In Solid Tumors (RECIST v1.0): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >/=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Bone marrow aspirations and biopsies were evaluated by histopathology and appropriate immunohistochemistry; Modified Curie score was used for MIBG evaluation.

Full Information

First Posted
October 25, 2011
Last Updated
July 22, 2019
Sponsor
Children's Mercy Hospital Kansas City
Collaborators
Center for Cell and Gene Therapy, Baylor College of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT01460901
Brief Title
Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma
Acronym
STALLONe
Official Title
Phase I Study of Donor Derived,Gene Modified, Multi-virus-specific, Cytotoxic T-Lymphocytes Redirected to GD2 for Relapsed/Refractory Neuroblastoma Post-allo Stem Cell Transplantation With Submyeloblative Conditioning
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
October 2012 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Children's Mercy Hospital Kansas City
Collaborators
Center for Cell and Gene Therapy, Baylor College of Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroblastoma
Keywords
Neuroblastoma, Relapsed, Refractory

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
GD2 CAR modified Tri-virus CTL infusion
Arm Type
Experimental
Arm Description
A single infusion of 2x10e6 cells per meter squared was performed 30 to 120 days following allogeneic stem cell transplant.
Intervention Type
Biological
Intervention Name(s)
GD2 CAR modified Tri-virus specific cytotoxic t-cells
Intervention Description
This is a feasibility study to assess safety of an infusion of chimeric-antigen receptor gene modified allogeneic virus specific T lymphocytes after reduced intensity allogeneic stem cell transplant. Three patients were treated and safety was evaluated. Patients received a single infusion of 2x10e6/m2 donor derived, GD2 CAR modified, tri-virus specific CTL performed 30-120 days after allogeneic stem cell transplantation
Primary Outcome Measure Information:
Title
Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks
Description
Immediate: Patients were monitored following infusion to assess for toxicity related to infusion. Potential toxicities related to cellular therapy infusions, such as allergic reaction to the cellular product or cryopreservation media, hemolytic reactions, volume overload, and hemodynamic instability, were monitored. Short Term: Patients were monitored for 8 weeks for short term toxicity related to infusion. Such adverse reactions monitored were acute graft versus host disease and cytokine release syndrome.
Time Frame
Post infusion week 8
Title
Peak Transgene Copy Number Per 1000ng PBMC DNA
Description
Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.
Time Frame
1 year
Title
Death Within 8 Weeks of Infusion
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well
Description
The following analyses were performed on peripheral blood samples from patients at protocol assigned time points (pre-infusion, post-infusion at 4 hrs, weeks 1,2,4,6 and 8, month 3, 6 and 12: ELISPOT assay for CMV, Adenovirus and EBV specific CTL reported as SFU (spot forming unit) per 2x10e5 mononuclear cells
Time Frame
up to 1 year
Title
Maximum Tumor Response (RECIST 1.1)
Description
Pre and post-therapy evaluation by modalities consistent with prior disease evaluation in each patient. When possible, tumors were assessed per Response Evaluation Criteria In Solid Tumors (RECIST v1.0): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >/=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Bone marrow aspirations and biopsies were evaluated by histopathology and appropriate immunohistochemistry; Modified Curie score was used for MIBG evaluation.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Months
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Doug Myers, MD
Organizational Affiliation
Children's Mercy Hospital Kansas City
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.childrensmercy.org/
Description
Children's Mercy Hospitals and Clinics

Learn more about this trial

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

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