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Targeting the IPA and Matching for the Non-Inherited Maternal Antigen for Haplo-Cord Transplantation

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ClinicalTrials.gov Identifier: NCT01810588
Recruitment Status : Recruiting
First Posted : March 13, 2013
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief Summary:

In this trial, we aim to improve the outcomes of haplo cord transplant. Haplo cord transplant is a novel and promising way to improve transplant outcomes. We hypothesize that identification of a graft that is at least 5/6 matched and inherited paternal antigen (IPA) targeted (i.e., cord blood grafts share one or more IPA antigens with the prospective recipient) is more important to the outcome of haplo cord transplant than the nucleated cell dose. The identification of such a graft for a large proportion of the subjects may necessitate accepting a lower umbilical cord graft dose.

In addition to a umbilical cord blood transplant, recipients will receive stem cells from a family member ( a haplo-identical donor) . After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. The subject will undergo a chemotherapy conditioning regimen prior to transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.


Condition or disease Intervention/treatment Phase
Hematologic Malignancies Device: CliniMACS® CD34 Reagent System Drug: Fludarabine Drug: Melphalan Drug: anti-thymocyte globulin (rabbit) Drug: Rituximab Radiation: Total Body Irradiation Drug: Mycophenolate Mofetil Drug: Tacrolimus Phase 2

Detailed Description:

This is a clinical trial for subjects with hematologic malignancies ( acute leukemia, myeloproliferative disorders, lymphoma, myeloma) who are in need of a donor stem cell transplant, and for whom an umbilical cord blood transplant is thought to be the best option. As donors for allogeneic transplant, we typically try to use related family members, such as brothers or sisters, or volunteer donors who are 'HLA matched', i.e. share similar proteins on their cells. This study is for subjects for whom such a matched sibling donor or a matched unrelated donor is not available.

For such subjects a commonly used transplant procedure is to use stem cells from one or two umbilical cords (UCB) from a newborn. These umbilical cord blood grafts, despite not completely matching the recipient, cause few problems with graft vs host disease (a common complication of transplant). But they tend to grow very slowly and subjects often have very prolonged hospital stays and are at high risk for complications due to low blood counts. Umbilical cord blood transplant will be the standard arm for this protocol.

This study uses a new method of bone marrow transplantation called combined haplo-identical cord (haplo-cord) transplantation. In this procedure, cells from a related donor who shares half of the HLA proteins ( haplo-identical) are collected from the blood, as well as cells from an umbilical cord, and then both are transplanted. It is hoped that by using cells from a haplo-identical relative, subjects will have a faster recovery and require fewer transfusions. Over time the haplo-identical cells from the relative are replaced by the cells from the cord blood. The combined transplantation of haplo-identical stem cells and cord blood has previously been used in approximately 60 subjects with very encouraging results.

Traditionally it has been felt that the most important determinant of outcome of an UCB stem cell transplant is the cord blood cell dose. The second determinant is the degree of matching between donor and recipient. Many times, we have difficulty identifying UCB units of sufficient cell dose that are well matched. Of interest,in our prior study of haplo-cord SCT indicated outcomes seemed independent of the UCB cell dose. If this preliminary observation is correct, we may be able to improve the outcomes of haplo cord transplant further by accepting lower threshold UCB doses and rather focusing on optimal matching (including matching for HLA and another characteristic called IPA). This is the primary objective of this study.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Study of Optimal Cord Selection for Haplo-Cord Transplantation: Targeting the Inherited Paternal Antigen (IPA) and Matching for the Non-Inherited Maternal Antigen (NIMA)
Actual Study Start Date : October 16, 2012
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: All Patients

Haplo-cord transplantation:

All subjects will receive a conditioning regimen of chemotherapy prior to stem cell transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.

For the transplant component of treatment, subject will receive umbilical cord blood. The study involves transplantation of unlicensed units of cord blood. Therefore, these are considered investigational products.

In addition to the umbilical cord blood unit, recipients will receive stem cells from a family member ( a haplo-identical donor). After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device.

Device: CliniMACS® CD34 Reagent System
The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose. The manufacturer of the device, Miltenyi Biotec, is providing the researchers access to the device for use in this research study. Because the stem cells from the haplo-identical donor are treated using the CliniMACS CD34 selection device, they cells are considered investigational.

Drug: Fludarabine
Administer 30 mg/m2 /day intravenously x 5 days (Day -7 to Day -3) of a total dose of 150 mg/m2. Fludarabine will be dosed according to actual body weight.
Other Name: Fludara, Fludarabine phosphate

Drug: Melphalan
Administer 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucositis

Drug: anti-thymocyte globulin (rabbit)
Administer 1.5 mg/kg/day intravenously x 3 days, total 4.5 mg/kg. ATG will be dosed according to actual body weight. The first dose will be infused over at least six hours, and subsequent doses over at least 4 hours. Pre-medications include acetaminophen 650 mg by mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration).
Other Name: rATG, Rabbit ATG

Drug: Rituximab
Administer one dose of 375 mg/m2 prior to or upon admission for all patients not previously exposed to rituximab or who have not received rituximab in the six months prior to transplant.
Other Name: Rituxan

Radiation: Total Body Irradiation
Patients at high risk of CNS relapse (e.g. ALL or Burkitt's lymphoma) or patients at high risk for graft rejection (i.e., donor-specific HLA antibodies, patients with severe aplastic anemia, or hemoglobinopathies) may receive 2 doses of TBI as part of the conditioning.
Other Name: TBI

Drug: Mycophenolate Mofetil
Will be started on Day -2 and given at a dose of 1000 mg every 8 hours until Day 28. Mycophenolae Mofetil can be given orally or intravenously. Infection, toxicity, very low patient weight (<50 kilograms) may prompt earlier discontinuation or adjustment of doses.
Other Name: Cellcept, MMF

Drug: Tacrolimus
Administered 0.03/mg/kg/day intravenous continious infusion (CI) over 24 hours from 4pm Day -2 until engraftment or when subject is able to take orally, then tacrolimus approximately 0.09 mg/kg orally in 2 divided doses. Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through Day 180, tapered by 20% every week thereafter. Infection, toxicity or other clinical circumstances may prompt earlier discontinuation or adjustment of doses. In the presence of Graft versus Host Disease, a clinical decision by the attending physician will determine if tacrolimus can be tapered or should be continued. Oral tacrolimus can be used when intravenous access for CI tacrolimus is unavailable.
Other Name: Prograf




Primary Outcome Measures :
  1. Lowest threshold of umbilical cord nucleated cell dose for haplo-cord transplants. [ Time Frame: 100 days ]
    We aim to identify the lowest threshold of umbilical cord nucleated cell dose that can be utilized assure durable umbilical cord blood engraftment in the haplo-cord transplants. The threshold will be defined as the lowest dose which assures cord blood engraftment occurs in at least 80% of subjects.


Secondary Outcome Measures :
  1. Long-term survival of subjects undergoing haplo-cord transplants [ Time Frame: 5 years after transplant ]
    Evaluate the long term outcome of subjects undergoing haplo cord transplants using an optimally matched umbilical cord blood (UCB) graft (i.e. Survival, profession-free survival (PFS), Relapse, transplant-related mortality (TRM), toxicities, infections and GVHD)

  2. Impact of IPA targeting on transplant outcome [ Time Frame: 5 years from transplantation ]
    As much as possible, UCB units will be chosen to be IPA targeted. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with IPA status.

  3. Impact of NIMA matching on transplant outcome [ Time Frame: 5 years from transplantation ]
    As much as possible, UCB units will be chosen to be NIMA matched. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with NIMA status.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject must have a confirmed diagnosis of:

    1. Previously Relapsed or refractory acute leukemia (myeloid or lymphoid)
    2. Acute leukemia in first remission at high-risk for recurrence
    3. Chronic myelogenous leukemia in chronic, accelerated phase or blast-crisis
    4. Recurrent or refractory malignant lymphoma or Hodgkin lymphoma
    5. Chronic lymphocytic leukemia, relapsed or with poor prognostic features
    6. Multiple myeloma
    7. Myelodysplastic syndrome
    8. Chronic myeloproliferative disease
    9. Hemoglobinopathies
    10. Aplastic anemia
    11. Other hematological disorder in need of allogeneic transplant (e.g. blastoid dendritic cell neoplasm)
  • Age ≥ 18 years
  • Likely to benefit from allogeneic transplant in the opinion of the transplant physician
  • An HLA-identical related or unrelated donor cannot be identified within an appropriate time frame.
  • Karnofsky (KPS) Performance status of >= 70%
  • Acceptable organ function as defined below: Serum bilirubin: < 2.0mg/dL ALT(SGPT): < 3 X upper limit of normal Creatinine Clearance: > 50 mL/min/1.73m2 (as estimated by the modified MDRD equation)
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Life expectancy is severely limited by concomitant illness or uncontrolled infection
  • Severely decreased Left Ventricular Ejection Fraction (LVEF) or impaired pulmonary function tests (PFT's)
  • Evidence of chronic active hepatitis or cirrhosis
  • Uncontrolled HIV disease
  • Pregnant or lactating

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): NCT01810588


Contacts
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Contact: June Greenberg, RN 212-746-2651 jdg2002@med.cornell.edu

Locations
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United States, Illinois
University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Linda Schroeder, MS, RN    773-834-0982    lschroed@medicine.bsd.uchicago.edu   
Principal Investigator: Andrew Artz,, MD, PhD         
United States, New York
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
Contact: June Greenberg, RN    212-746-2651    jdg2002@med.cornell.edu   
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
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Principal Investigator: Koen van Besien, MD, PhD Weill Medical College of Cornell University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01810588     History of Changes
Other Study ID Numbers: 1205012383
First Posted: March 13, 2013    Key Record Dates
Last Update Posted: March 26, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Weill Medical College of Cornell University:
Allogeneic transplant
Hematologic Malignancies
Acute Leukemia
Myeloproliferative disorders
Lymphoma
Myeloma

Additional relevant MeSH terms:
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Neoplasms
Rituximab
Tacrolimus
Fludarabine phosphate
Melphalan
Antilymphocyte Serum
Thymoglobulin
Fludarabine
Mycophenolic Acid
Vidarabine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents