Clinical Trials /

Alpha/Beta CD19+ Depleted Haploidentical Transplantation + Zometa for Pediatric Hematologic Malignancy's and Solid Tumors

NCT02508038

Description:

This phase I trial studies the safety of transplantation with a haploidentical donor peripheral blood stem cell graft depleted of TCRαβ+ cells and CD19+ cells in conjunction with the immunomodulating drug, Zoledronate, given in the post-transplant period to treat pediatric patients with relapsed or refractory hematologic malignancies or high risk solid tumors.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Ewing Sarcoma
  • Extracranial Neuroblastoma
  • Hodgkin Lymphoma
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Neuroblastoma
  • Non-Hodgkin Lymphoma
  • Osteosarcoma
  • Primitive Neuroectodermal Tumor
  • Rhabdomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TCRαβ+/CD19+ Depleted Haploidentical HSCT + Zoledronate
  • Official Title: TCR-αβ+ and CD19+ Depleted KIR/KIR Ligand-mismatched Haploidentical Hematopoietic Stem Cell Transplant and Zoledronate for Pediatric Relapsed/Refractory Hematologic Malignancies and High Risk Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: UW13090
  • SECONDARY ID: NCI-2015-01163
  • NCT ID: NCT02508038

Conditions

  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Hodgkin Lymphoma
  • Non-Hodgkin Lymphoma
  • Myelodysplastic Syndrome
  • Myeloproliferative Syndrome
  • Rhabdomyosarcoma
  • Ewing Sarcoma
  • Primitive Neuroectodermal Tumor
  • Osteosarcoma
  • Neuroblastoma

Interventions

DrugSynonymsArms
ZoledronateZoledronic Acid, ZometaTCRαβ+/CD19+ depleted Haploidentical HSCT+ Zoledronate

Purpose

This phase I trial studies the safety of transplantation with a haploidentical donor peripheral blood stem cell graft depleted of TCRαβ+ cells and CD19+ cells in conjunction with the immunomodulating drug, Zoledronate, given in the post-transplant period to treat pediatric patients with relapsed or refractory hematologic malignancies or high risk solid tumors.

Detailed Description

      REDUCED-INTENSITY CONDITIONING REGIMEN: Patients receive anti-thymocyte globulin (ATG)
      intravenously (IV) on days -12 to -9, fludarabine phosphate IV on days -8 to -5, thiotepa IV
      twice daily (BID) on day -4, and melphalan IV on days -3 to -2.

      PERIPHERAL BLOOD STEM CELL TRANSPLANTATION: Patients undergo TCR-αβ+ and CD19+ depleted
      haploidentical donor peripheral blood stem cell transplantation on day 0.

      ZOLEDRONATE ADMINISTRATION: Patients receive zoledronate IV after transplant as determined by
      their assigned treatment group (Cohort). Patients in Cohort A do not receive zoledronate.

      Follow-up assessments will occur after transplantation.
    

Trial Arms

NameTypeDescriptionInterventions
TCRαβ+/CD19+ depleted Haploidentical HSCT+ ZoledronateExperimentalPatients will undergo a reduced-intensity conditioning regimen consisting of ATG, Fludarabine, Thiotepa, and Melphalan prior to transplant with a KIR/KIR ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCR-αβ+ and CD19+ cells. Patients (except those in Cohort A) will receive two doses of Zoledronate (at a 28 day interval) following transplant. Dose and post-transplant timing of Zoledronate administration is dependent upon patient Cohort.
  • Zoledronate

Eligibility Criteria

        Inclusion Criteria:

        Availability of an eligible haploidentical donor

        Hematologic malignancy

        Patients with hematologic malignancy must have no HLA identical sibling or suitable
        unrelated donor OR time needed to find an acceptable unrelated donor match would likely
        result in disease progression such that the patient may become ineligible for any type of
        potentially curative transplant

          -  Relapsed or primary therapy-refractory AML with bone marrow blast < 20%

          -  High-risk refractory or relapsed ALL in patients for whom transplantation is deemed
             indicated (primary induction failure or hypodiploidy, relapse occurring < 30 months
             from diagnosis, relapse after previous allogeneic hematopoietic stem cell transplant
             [allo-HSCT], relapse after 2nd remission)

          -  Relapsed Hodgkin lymphoma unable to achieve 2nd remission or Very Good Partial
             Response (VGPR) and therefore ineligible to receive autologous hematopoietic stem cell
             transplant (auto-HSCT)

          -  Hodgkin lymphoma relapsing after auto-HSCT

          -  Primary refractory or relapsed non-Hodgkin lymphoma unable to achieve 2nd remission or
             VGPR and therefore ineligible to receive auto-HSCT

          -  Non-Hodgkin lymphoma relapsing after auto-HSCT

          -  Myelodysplastic Syndrome/Myeloproliferative Syndrome

        Solid Tumor

        Patients with solid tumor must have failed or have been ineligible to receive auto-HSCT or
        if auto-HSCT would not offer > 20% chance of cure

          -  Neuroblastoma

               -  high risk with relapsed or refractory disease

          -  Soft tissue sarcomas (Rhabdomyosarcoma, Ewing sarcoma, Primitive Neuroectodermal Tumor
             or other high-risk extracranial solid tumors)

               -  Relapsed or primary refractory metastatic

               -  1st complete remission, but very high-risk features (i.e., < 20% survival with
                  conventional therapy)

          -  Osteosarcoma

               -  Failure to achieve Complete Response (CR) following initial therapy

               -  Relapsed with pulmonary or bone metastases and did not achieve a CR with surgery
                  and/or chemotherapy

        Karnofsky (patients > 16 years) or Lansky (patients 16 years or older) performance score of
        ≥ 60

        Life expectancy of ≥ 3 months

        Patient must have fully recovered from acute toxic effects of all prior chemotherapy,
        immunotherapy, or radiotherapy prior to entering this study

        Study enrollment no earlier than 3 months after preceding HSCT

        Glomerular Filtration Rate (GFR) ≥ 60 ml/min/1.73m2

        Total bilirubin < 3 mg/dL

        ALT (alanine aminotransferase, SCPT) ≤ 5 x Upper LImit of Normal (ULN) for age

        Ejection fraction of > 40% by Multigated Acquisition Scan (MUGA) or echocardiogram

        No evidence of dyspnea at rest

        No supplemental oxygen requirement

        If measured, carbon monoxide diffusion capacity (DLCO) >50%

        No severe peripheral neuropathy, signs of leukoencephalopathy or active Central Nervous
        System (CNS) infection

        Patients with seizure disorders may be enrolled if seizures are well controlled on
        anticonvulsant therapy

        If of reproductive potential, negative pregnancy test and willing to use effective birth
        control method

        Informed consent from patient or legal guardian (if patient is minor)

        Exclusion Criteria:

        Pregnant or breast-feeding

        HIV infection

        Heart failure or uncontrolled cardiac rhythm disturbance

        Uncontrolled, Serious Active Infection

        Prior organ allograft

        Significant serious intercurrent illness unrelated to cancer or its treatment not covered
        by other exclusion criteria expected to significantly increase the risk of HSCT

        Any mental or physical condition, in the opinion of the PI (or PI designee), which could
        interfere with the ability of the subject (or the only parent or legal guardian available
        to care for the subject) to understand or adhere to the requirements of the study

        Enrollment in any other clinical study from screening up to Day 100 (unless PI judges such
        enrollment would not interfere with endpoints of this study)
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:7 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of acute graft versus host disease (GVHD)
Time Frame:Within 100 days post-transplantation
Safety Issue:
Description:Neutrophil engraftment is defined by Absolute Neutrophil Count (ANC) cell count and time to reach ANC greater than 500 for three consecutive days.

Secondary Outcome Measures

Measure:Immune reconstitution
Time Frame:Up to 2 years
Safety Issue:
Description:Immune reconstitution outcomes, as determined by immune cell analysis.
Measure:Performance of the CliniMACS Reagent System utilizing the CliniMACS TCRαβ-biotin and CliniMACS CD19 reagent to produce a graft with defined cell content.
Time Frame:Day 0
Safety Issue:
Description:The performance of the CliniMACS Reagent System will be evaluated by measuring the number of viable stem cells, TCRαβ+ cells, TCRγ&#948;+ cells, NK cells and B cells in the hematopoietic stem cell graft.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Wisconsin, Madison

Trial Keywords

  • alpha beta depleted
  • alphabeta
  • TCR alpha beta depleted
  • alpha beta
  • haploidentical
  • Zoledronate
  • Zoledronic acid
  • Pediatric cancers
  • alfa beta
  • αβ T cell depleted HSCT
  • alpha beta T cell and B cell depleted HSCT
  • haploidentical HSCT

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