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TCRαβ+/CD19+ Depleted Haploidentical HSCT + Zoledronate

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ClinicalTrials.gov Identifier: NCT02508038
Recruitment Status : Recruiting
First Posted : July 24, 2015
Last Update Posted : April 19, 2017
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Hodgkin Lymphoma Non-Hodgkin Lymphoma Myelodysplastic Syndrome Myeloproliferative Syndrome Rhabdomyosarcoma Ewing Sarcoma Primitive Neuroectodermal Tumor Osteosarcoma Neuroblastoma Procedure: TCRαβ+/CD19+ depleted Haploidentical HSCT Drug: Zoledronate Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : January 2016
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : November 2020

Arm Intervention/treatment
Experimental: TCRαβ+/CD19+ depleted Haplo-HSCT+ Zoledronate
Patients 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.
Procedure: TCRαβ+/CD19+ depleted Haploidentical HSCT
Patients will undergo a reduced-intensity conditioning regimen prior to transplant with a haploidentical donor peripheral blood stem cell graft depleted of TCRαβ+ cells and CD19+ cells using the CliniMACS System.
Drug: Zoledronate
Given IV. 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.
Other Names:
  • Zoledronic Acid
  • Zometa

Primary Outcome Measures :
  1. Incidence of acute graft versus host disease (GVHD) [ Time Frame: Within 100 days post-transplantation ]
  2. Incidence of neutrophil engraftment [ Time Frame: Up to day 28 ]
    Neutrophil engraftment is defined by Absolute Neutrophil Count (ANC) cell count and time to reach ANC greater than 500 for three consecutive days.

  3. Incidence of platelet engraftment [ Time Frame: Up to day 28 ]
    Platelet engraftment is as defined by platelet count and time to reach more than or equal to 20,000 for three consecutive days, without platelet transfusions for 7 days.

  4. Incidence of graft failure [ Time Frame: At day 28 ]
  5. Determination of Maximal Tolerated Dose (MTD) of zoledronic acid in the post-HSCT period [ Time Frame: Up to day 119 ]

Secondary Outcome Measures :
  1. Immune reconstitution [ Time Frame: Up to 2 years ]
    Immune reconstitution outcomes, as determined by immune cell analysis.

  2. 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 ]
    The performance of the CliniMACS Reagent System will be evaluated by measuring the number of viable stem cells, TCRαβ+ cells, TCRγδ+ cells, NK cells and B cells in the hematopoietic stem cell graft.

Information from the National Library of Medicine

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Ages Eligible for Study:   7 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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)

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): NCT02508038

Contact: Jenny Weiland 608-890-8070 PedsHemOncResearch@lists.wisc.edu
Contact: Celeste Matsushima 608-890-8069

United States, Wisconsin
University of Wisconsin Carbone Cancer Center Recruiting
Madison, Wisconsin, United States, 53705
Contact: Pediatric HemOnc Main Line    608-263-6200    PEDSHemOncResearch@lists.wisc.edu   
Contact: Research Office    608-890-8070    PEDSHemOncResearch@lists.wisc.edu   
Principal Investigator: Mario Otto, MD, PhD         
Sponsors and Collaborators
University of Wisconsin, Madison
Principal Investigator: Mario Otto, MD, PhD University of Wisconsin, Madison

Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT02508038     History of Changes
Other Study ID Numbers: UW13090
NCI-2015-01163 ( Registry Identifier: NCI CTRP )
First Posted: July 24, 2015    Key Record Dates
Last Update Posted: April 19, 2017
Last Verified: April 2017

Keywords provided by University of Wisconsin, Madison:
alpha beta depleted
TCR alpha beta depleted
alpha beta
Zoledronic acid
Pediatric cancers
alfa beta
αβ T cell depleted HSCT
alpha beta T cell and B cell depleted HSCT
haploidentical HSCT

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Hodgkin Disease
Sarcoma, Ewing
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Myeloproliferative Disorders
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neuroectodermal Tumors, Primitive, Peripheral