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Engineered Neuroblastoma Cellular Immunotherapy (ENCIT)-01

This study is currently recruiting participants.
Verified January 2017 by Julie Park, Seattle Children's Hospital
Sponsor:
ClinicalTrials.gov Identifier:
NCT02311621
First Posted: December 8, 2014
Last Update Posted: February 1, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
EVAN Foundation
Ben Towne Center for Childhood Cancer Research
Information provided by (Responsible Party):
Julie Park, Seattle Children's Hospital
  Purpose
Patients with recurrent or refractory neuroblastoma are resistance to conventional chemotherapy. For this reason, the investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the neuroblastoma cell through the recognition of CD171, a protein expressed of the surface of the neuroblastoma cell in patients with neuroblastoma. This is a phase 1 study designed to determine the maximum tolerated dose of the CAR+ T cells.

Condition Intervention Phase
Neuroblastoma Ganglioneuroblastoma Biological: Patient Derived CD171 specific CAR T cells expressing EGFRt (2nd generation T cells) Biological: Patient Derived CD171 specific CAR T cells expressing EGFRt (3rd generation T cells) Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Feasibility and Safety Study of Cellular Immunotherapy for Recurrent/Refractory Neuroblastoma Using Autologous T-cells Lentivirally Transduced to Express CD171-specific Chimeric Antigen Receptors

Resource links provided by NLM:


Further study details as provided by Julie Park, Seattle Children's Hospital:

Primary Outcome Measures:
  • Dose Limiting Toxicity [ Time Frame: 28 days ]
    Patients will be evaluated through day 28 for occurrence of dose limiting toxicity


Secondary Outcome Measures:
  • Response (Tumor response will be evaluated by the revised International Neuroblastoma Response Criteria) [ Time Frame: 42 days ]
    Tumor response will be evaluated by the revised International Neuroblastoma Response Criteria


Estimated Enrollment: 40
Study Start Date: November 2014
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A: 2nd Generation CE7R CAR T Cells

Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt.

Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy.

Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10^6 cells/kg, 5x10^6 cells/kg, 1x10^7 cells/kg, 5x10^7 cells/kg, and 1x10^8 cells/kg will be evaluated.

Biological: Patient Derived CD171 specific CAR T cells expressing EGFRt (2nd generation T cells)
Intravenous infusion of autologous T cells transduced to express 4-1BB:zeta CD171CAR and EGFRt (2nd generation T cells)
Experimental: B: 3rd Generation CE7R CAR T Cells

Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt.

Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy.

Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10^6 cells/kg, 5x10^6 cells/kg, 1x10^7 cells/kg, 5x10^7 cells/kg, and 1x10^8 cells/kg will be evaluated.

Biological: Patient Derived CD171 specific CAR T cells expressing EGFRt (3rd generation T cells)
Intravenous infusion of autologous T cells transduced to express CD28:4-1BB:zeta CD171CAR and EGFRt

Detailed Description:

Upon meeting the eligibility requirements and enrolling on study, subjects will undergo apheresis to obtain the T cells for the generation of the CD171 CAR+ T cells. The T cells are isolated from the apheresis product, the CD4 and CD8 T cells are then selected and grown separately, transduced with a lentivirus to express the CD171 CAR as well as a truncated EGFR that has no signaling capacity (noted EGFRt) and expanded in culture over a 4-6 week period. During the process of cell generation, subjects will continue to be cared for by their primary oncologist and may undergo additional treatment directed at neuroblastoma during this time.

After the CAR+ T cells have been generated, the subject undergoes a disease assessment and determination of necessary lymphodepletion therapy. A variety of lymphodepletion strategies are acceptable and determined on a case by case basis. At least 48 hours after the completion of lymphodepletion, the subject will receive and infusion of CAR+ T cells at an approximate 1:1 ratio of CD4 to CD8 CAR+ T cells.

Following treatment with the CAR+ T cells, subjects will be followed intensely for 6 weeks with serial blood testing and re-evaluation of disease status with MIBG scintigraphy, tumor imaging by MRI/CT and bone marrow aspirates. After 4-6 weeks, the subjects clinical care will be resumed by their primary oncologist, and it is possible that they would receive additional chemotherapy or investigational agents.

Some subjects will receive cetuximab for ablation of the genetically modified T cells. Criteria to receive cetuximab include acute toxicities that are life threatening, as well as studies indicating lymphoproliferative disorder arising from an infused genetically modified T cell.

Upon completion of the study, subjects will be followed bi-annually for 5 years, and then annually for 10 additional years with either a medical history, physical exam and blood tests or a phone call/questionnaire. This follow up will help to determine if the subject develops any long-term health problems related to the CAR+ T cells including a new cancer.

  Eligibility

Information from the National Library of Medicine

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

Inclusion Criteria:

Patient must have a documentation of prior diagnosis of NB or ganglioneuroblastoma either by histologic verification and/or demonstration of tumor cells in the bone marrow with increased catecholamine levels.

Male or female subjects ≤ 18 years of age at the time of study enrollment.

Patient must have had a diagnosis of high risk NB at initial diagnosis or if non-high risk at time of initial diagnosis must have had evidence of metastatic progression when > 18 months of age.

Patient must have measurable or evaluable disease occurring as one of the following:

  • Disease progression after initiation of upfront NB therapy defined as:
  • New disease site documented on MIBG scintigraphy; or CT/MRI; or any new bone site that is FDG-PET avid (in patient known to have MIBG non-avid tumor) AND has MRI findings consistent with tumor OR has a biopsy showing NB or ganglioneuroblastoma;
  • Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI AND a minimum absolute increase of 5 mm in longest dimension in existing lesions;
  • Bone marrow biopsy meeting revised INRC criteria for progressive disease.
  • Refractory disease such that response to upfront therapy (defined as at least 4 cycles of muti-agent induction chemotherapy) is less than partial response.
  • Persistence of disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by MIBG scan, CT/MRI, or bone marrow aspirate/biopsies). Patients in this category are REQUIRED to have histologic confirmation of viable NB from at least one residual site. Tumor seen on routine bone marrow morphology is sufficient.

Patient must have a Lansky performance status score of ≥ 50 (appendix I). Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Patient must have a life expectancy of ≥ 8 weeks.

Patient must, in the opinion of the study PI or designee, have fully recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment onto this study.

Must be at least 7 days since last chemotherapy or biologic therapy administered. For patients previously enrolled on this trial who had a usable T cell product generated but removed prior to receiving T cell therapy and are re-enrolling on the trial, the time from chemotherapy agent or biologic agent is not restricted.

No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment.

At least 3 half-lives from time of last dose of anti-tumor directed antibody therapy or 30 days, whichever is shorter.

At least 6 weeks from myeloablative therapy and autologous stem cell transplant (timed from stem cell infusion). Patients who received stem cell infusion following non-myelo-ablative therapy are eligible once they meet all other eligibility requirements. Patient must NOT have received a prior allogeneic hematopoietic stem cell transplant.

No prior genetically modified cell therapy that is still detectable or prior virotherapy.

Must not be receiving external beam radiation therapy at the time of study enrollment. Must be at least 12 weeks from prior I131 MIBG therapy.

Normal serum creatinine based on age/gender as defined by SCH chemistry lab

Normal serum sodium level without need for supplementation

Total Bilirubin: ≤3x upper limit of normal (ULN) for age OR conjugated bilirubin ≤2mg/dl

ALT (SGPT): ≤5x the ULN.

Adequate cardiac function defined as shortening fraction >28% by echocardiogram or an ejection fraction >50% by MUGA.

Adequate Absolute Lymphocyte count (ALC) defined as: ALC ≥ 100 cells/µl

Documented negative HIV antigen and antibody, Hepatitis B surface antigen and Hepatitis C antibody within 3 months prior to enrollment. For patients with positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible.

Adequate Respiratory function defined as not requiring supplemental oxygen or mechanical ventilation; oxygen saturation 90% or higher on room air; no dyspnea at rest.

Patient does NOT have a history of relevant CNS pathology or current relevant CNS pathology (non-febrile seizure disorder requiring ongoing anti-epileptic medications, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder). Patients may have CNS intracranial tumor.

Patient is NOT pregnant or breast-feeding. Fertile patient MUST agree to use contraception during and for 12 months after T cell infusion.

Patient is able to tolerate apheresis procedure including placement of temporary apheresis catheter if necessary or has prior apheresis product of 50x10^6 MNC cells available for use.

Patient does NOT have an active malignancy other than NB.

Patient does NOT have known intracranial metastatatic neuroblastoma. Skull based disease with soft tissue extension is allowed.

Patient must NOT have an active severe infection defined as:

  • A positive blood culture within 48 hours of study enrollment
  • A fever above 38.2C AND clinical signs of infection within 48 hours of study enrollment

Patient does NOT have any concurrent medical condition that, in the opinion of the protocol PI or designee, would prevent the patient from undergoing protocol-based therapy. Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial.

Patient is NOT receiving any other anti-cancer agents or radiotherapy at the time of study entry.

Patient and/or parents or authorized legal representative have signed a written informed consent/assent per institutional guidelines.

Research participant or parent/legal guardian must agree to participate in long-term follow-up for up to 15 years, if they are enrolled in the study and receive T-cell infusion.

  Contacts and Locations
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): NCT02311621


Contacts
Contact: Heidi Ullom, RN 206-987-2553 immunotherapy@seattlechildrens.org
Contact: Renee Rivers 206-884-1029 immunotherapy@seattlechildrens.org

Locations
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Julie Park    206-987-2106      
Sponsors and Collaborators
Seattle Children's Hospital
EVAN Foundation
Ben Towne Center for Childhood Cancer Research
Investigators
Principal Investigator: Julie Park, MD Seattle Children's
  More Information

Responsible Party: Julie Park, Investigator, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT02311621     History of Changes
Other Study ID Numbers: ENCIT-01
First Submitted: December 4, 2014
First Posted: December 8, 2014
Last Update Posted: February 1, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Current plan will be to present as a combined data set once enrollment and assessments are complete. Individual data may be made available if clinically applicable based on extreme response or toxicity.

Additional relevant MeSH terms:
Neuroblastoma
Ganglioneuroblastoma
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