Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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.
 
ClinicalTrials.gov Identifier: NCT02508038
Recruitment Status : Recruiting
First Posted : July 24, 2015
Last Update Posted : March 20, 2019
Sponsor:
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:

CONDITIONING REGIMENS: Patients with high-risk leukemia will receive myeloablative conditioning with anti-thymocyte globulin intravenously (IV) over 4-6 hours on days -12 through -9, Fludarabine IV over 30 minutes on days -8 through -5, Thiotepa IV every every 12 hours on day -4 and Total Body Irradiation (TBI) on days -3 through -1. All other patients receive reduced intensity conditioning consisting of anti-thymocyte globulin intravenously (IV) over 4-6 hours on days -12 through -9, fludarabine IV over 30 minutes on days -8 through -5, thiotepa IV over 4 hours every 12 hours on day -4, and melphalan IV on days -3 and -2.

PERIPHERAL BLOOD STEM CELL TRANSPLANTATION: Patients undergo TCR-alpha/beta+ and CD19+ depleted KIR/KIR ligand-mismatched haploidentical donor peripheral blood stem cell transplantation on day 0. If the graft contains less than 4 x 10^6 CD34+ cells/kg, a second HSC graft may be administered.

PROPHYLAXIS FOR GVHD: Patients receiving a graft containing > 25 x 10^3 CD3+ TCR alpha/beta+ cells receive mycophenolate mofetil IV twice daily over 2 hours on days 1 to 30 with a rapid taper. Patients with TCR alpha/beta+ cells exceeding 100,000/kg also receive tacrolimus IV continuously or orally (PO) every 12 hours on days 0-90 with a taper at the discretion of the Principal Investigator.

ZOLEDRONATE ADMINISTRATION: Patients will receive five doses of Zoledronate (IV) at 28 day intervals beginning on Day +28 post-HSCT.

Follow-up assessments will occur after transplantation.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 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 2021
Estimated Study Completion Date : November 2023


Arm Intervention/treatment
Experimental: TCRαβ+/CD19+ depleted Haploidentical HSCT+ Zoledronate
Patients with high-risk leukemia (who are at least one year of age and who have not received TBI as conditioning for a previous HSCT) will receive myeloablative conditioning with ATG, Gludarabine, Thiotepa, and TBI. All other subjects 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 will receive 5 doses of zoledronate (at 28 day intervals) starting 28 days after stem cell transplant.
Procedure: TCRαβ+/CD19+ depleted Haploidentical HSCT
Patients with high-risk leukemia will receive myeloablative conditioning. All other patients will undergo a reduced-intensity conditioning with ATG, Fludarabine, Thiotepa and TBI followed by transplant with a KIR/KIR (Killer cell immunoglobulin-like recetptor) ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCRab+ cells and CD19+ cells using the CliniMACS System. All other patientw will undergo a reduced-intensity conditioning regimen consisting of ATG, Fludarabine, Thiotep and Melphalan followed by haploidentical transplant.

Drug: Zoledronate
Given IV. Patients will receive five doses of Zoledronate (each 1.25 mg/m2 at a 28 day interval) following transplant.
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 ]

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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Availability of an eligible haploidentical donor
  • Hematologic malignancy or solid tumor
  • Patients with more than one malignancy (hematologic or solid tumor) are eligible
  • 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 (relapse occurring < 30 months from diagnosis, patients relapsing after previous allogeneic transplant, relapse after 2nd remission, primary induction failure or hypodiploidy)
    • 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)

Inclusion Criteria for Donors:

  • Donor must be 18 years or older
  • Donor must be in good general health as determined by evaluating medical provider
  • Must meet donor criteria for human cells, tissues, and cellular and tissue-based products per Code of Federal Regulations 21 CFR 1271, subpart C. Specifically:

    • Donor screening in accordance with 1271.75 indicates that the donor:

      • Is free from risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases; and
      • Is free from communicable disease risks associated with xenotransplantation; and
    • The results of donor testing for relevant communicable disease agents in accordance with 1271.80 and 1271.85 are negative or nonreactive, except as provided in 1271.80(d)(1).
  • Haploidentical by HLA-typing
  • Preference will be given to donors who demonstrate KIR incompatibility with recipient HLA class I ligands defined as the donor expressing a KIR gene for which the corresponding HLA class I ligand is not expressed by the recipient.
  • Negative testing for relevant communicable diseases:

    • Hepatitis B surface antigen (HBsAg)
    • Hepatitis B core antibody (Anti-HBc)
    • Hepatitis C antibody (Anti-HCV)
    • HIV 1 & 2 antibody (Anti-HIV-1, 2 plus O)
    • HTLV I/II antibody (Anti-HTLV I/II)
    • RPR (Syphilis TP)
    • CMV (Capture CMV)
    • MPX for: HepB (HBV-PCR), HepC (HCV-PCR), HIV (HIV-PCR)
    • NAT for West Nile Virus (WNV-PCR)
    • T. Cruzi - EIA (Chagas)

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)

Exclusion Criteria for Donors:

  • Lactating females
  • Pregnant females

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


Contacts
Layout table for location contacts
Contact: Jenny Weiland 608-890-8070 PedsHemOncResearch@lists.wisc.edu
Contact: Celeste Matsushima 608-890-8069

Locations
Layout table for location information
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
Investigators
Layout table for investigator information
Principal Investigator: Mario Otto, MD, PhD University of Wisconsin, Madison

Layout table for additonal information
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: March 20, 2019
Last Verified: March 2019
Keywords provided by University of Wisconsin, Madison:
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neuroblastoma
Osteosarcoma
Rhabdomyosarcoma
Sarcoma, Ewing
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Myelodysplastic Syndromes
Syndrome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Sarcoma
Neoplasms, Connective and Soft Tissue
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Neuroepithelial
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Bone Tissue