Clinical Trials /

Engineered Neuroblastoma Cellular Immunotherapy (ENCIT)-01

NCT02311621

Description:

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.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Engineered Neuroblastoma Cellular Immunotherapy (ENCIT)-01
  • 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

Clinical Trial IDs

  • ORG STUDY ID: ENCIT-01
  • NCT ID: NCT02311621

Conditions

  • Neuroblastoma
  • Ganglioneuroblastoma

Interventions

DrugSynonymsArms
Patient Derived CD171 specific CAR T cells expressing EGFRt (2nd generation T cells)A: 2nd Generation CE7R CAR T Cells
Patient Derived CD171 specific CAR T cells expressing EGFRt (3rd generation T cells)B: 3rd Generation CE7R CAR T Cells

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
A: 2nd Generation CE7R CAR T CellsExperimentalAutologous 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.
    B: 3rd Generation CE7R CAR T CellsExperimentalAutologous 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.

      Eligibility 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.
            
      Maximum Eligible Age:18 Years
      Minimum Eligible Age:18 Months
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Dose Limiting Toxicity
      Time Frame:28 days
      Safety Issue:
      Description:Patients will be evaluated through day 28 for occurrence of dose limiting toxicity

      Secondary Outcome Measures

      Measure:Response (Tumor response will be evaluated by the revised International Neuroblastoma Response Criteria)
      Time Frame:42 days
      Safety Issue:
      Description:Tumor response will be evaluated by the revised International Neuroblastoma Response Criteria

      Details

      Phase:Phase 1
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Seattle Children's Hospital

      Last Updated

      January 30, 2017