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Non-Myeloablative Conditioning and Bone Marrow Transplantation

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01850108
Recruitment Status : Suspended (COVID-19 response)
First Posted : May 9, 2013
Last Update Posted : June 11, 2020
Sponsor:
Information provided by (Responsible Party):
Adetola A. Kassim, Vanderbilt-Ingram Cancer Center

Tracking Information
First Submitted Date  ICMJE May 1, 2013
First Posted Date  ICMJE May 9, 2013
Last Update Posted Date June 11, 2020
Study Start Date  ICMJE May 2013
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2013)
Transplant-related mortality (TRM) [ Time Frame: at 1 year after BMT ]
Defined as death in the absence of recurrent sickle cell disease or hemoglobinopathy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2018)
  • Progression-free survival [ Time Frame: 2 years ]
    Development of grade II-IV acute graft-vs.-host disease, confirmed histologically by a pathologist.
  • Characterize donor hematopoietic chimerism in peripheral blood after mini-haploBMT [ Time Frame: at days ~30, ~60, ~100 and ~180 after mini-haploBMT ]
    Partially human leukocyte antigen (HLA)-mismatched bone marrow from first-degree relatives. Defined in percentages of donor cells in patient's peripheral blood, measured in 4 ways.
    • Mixed donor chimerism: > 0% but < 95%
    • Complete donor chimerism > 95%
    Any amount of donor chimerism after day 60 will be considered as having engrafted
  • Characterize hematologic and non-hematologic toxicities of minihaploBMT [ Time Frame: Day 60 after BMT ]
    Hematologic toxicity: -Absolute neutrophil count (ANC): consecutive values of < 500/µL on 3 different days after chemotherapy post-BMT Platelet count: consecutive values of < 20,000 µL on 3 different days after chemotherapy post-BMT Non-hematologic toxicities: -Toxicities necessitating hospitalization Toxicities grade 4 or above Meets the criteria of the following SAE:
    • Relapse of underlying disease
    • Grade 3 ocular toxicity not related to ocular GVHD
    • Grade 3 related non-hematologic toxicity
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2013)
  • Progression-free survival [ Time Frame: 2 years ]
    Development of grade II-IV acute graft-vs.-host disease, confirmed histologically by a pathologist.
  • Characterize donor hematopoietic chimerism in peripheral blood after mini-haploBMT [ Time Frame: at days ~30, ~60, and ~180 after mini-haploBMT ]
    Partially human leukocyte antigen (HLA)-mismatched bone marrow from first-degree relatives. Defined in percentages of donor cells in patient's peripheral blood, measured in 4 ways.
    • Mixed donor chimerism: > 0% but < 95%
    • Complete donor chimerism > 95%
    Any amount of donor chimerism after day 60 will be considered as having engrafted
  • Characterize hematologic and non-hematologic toxicities of minihaploBMT [ Time Frame: Day 60 after BMT ]
    Hematologic toxicity: -Absolute neutrophil count (ANC): consecutive values of < 500/µL on 3 different days after chemotherapy post-BMT Platelet count: consecutive values of < 20,000 µL on 3 different days after chemotherapy post-BMT Non-hematologic toxicities: -Toxicities necessitating hospitalization Toxicities grade 4 or above Meets the criteria of the following SAE:
    • Relapse of underlying disease
    • Grade 3 ocular toxicity not related to ocular GVHD
    • Grade 3 related non-hematologic toxicity
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Non-Myeloablative Conditioning and Bone Marrow Transplantation
Official Title  ICMJE A Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Disease and Other Hemoglobinopathies
Brief Summary Allogeneic blood or marrow transplantation (alloBMT) is a curative therapy for a variety of hematologic disorders, including sickle cell disease and thalassemia. Even when it is clear that alloBMT can give to these patients an improvement in their disease, myeloablative transplants have important toxicities and mortalities associated. The lack of suitable donors continues to be a limit to access to transplantation. Substantial progress has been made recently in the development of pre-treatment regimens that facilitate the sustained engraftment of donor marrow with reduced toxicity. Most of these regimens incorporate highly immunosuppressive drugs, which allow the reduction or elimination of myeloablative agents or total body irradiation without endangering the sustained engraftment of HLA-identical allogeneic stem cells. Preliminary results of non-myeloablative allogeneic stem cell transplantation suggest that the procedure can be performed in patients who are ineligible for myeloablative alloBMT, and that sustained remissions of several hematologic malignancies can be obtained.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell Disease
  • Hemoglobinopathies
Intervention  ICMJE
  • Drug: Thymoglobulin

    Day 9 - 0.5 mg/kg IV before BMT

    Days 8 & 7 - 2mg/kg IV before BMT

  • Drug: Fludarabine
    On Days -6 to -2 before BMT, 30 mg/m2/day IV
    Other Name: Fludara®
  • Drug: Cyclophosphamide (CTX)
    Days 6 & 5 before BMT, 14.5 mg/kg IV; 50 mg/kg each day on 3rd & 4th day after BMT
    Other Name: Cytoxan
  • Drug: Mesna
    Days 3 & 4 after BMT: 40 mg/kg IV
  • Drug: Sirolimus
    Adjusted to maintain a serum trough level of 3-12 ng/mL, taken orally beginning on 5 days after BMT and taken to 1 year after BMT.
    Other Name: rapamycin, Rapamune®
  • Drug: Mycophenolate mofetil (MMF)
    15 mg/kg orally with maximum dose 3 mg/day beginning 5 days after BMT and taken to day 35 after BMT
  • Procedure: Bone marrow transplantation
    Day 0 - Transplantation of hematopoietic cells derived from bone marrow of a donor to a recipient as treatment for hematologic disorders
  • Radiation: Total body irradiation
    200 cGy on the day before BMT. Radiation delivered to the entire body of the recipient to eradicate bone marrow cells in the recipient to prepare the recipient to receive the transplanted
Study Arms  ICMJE Experimental: Non-Myeloablative Conditioning and Bone Marrow Transplantation
Interventions:
  • Drug: Thymoglobulin
  • Drug: Fludarabine
  • Drug: Cyclophosphamide (CTX)
  • Drug: Mesna
  • Drug: Sirolimus
  • Drug: Mycophenolate mofetil (MMF)
  • Procedure: Bone marrow transplantation
  • Radiation: Total body irradiation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: May 11, 2016)
25
Original Estimated Enrollment  ICMJE
 (submitted: May 8, 2013)
8
Estimated Study Completion Date  ICMJE March 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

RECIPIENT INCLUSION CRITERIA

  • Patients who are ineligible for BMT from an HLA-matched sibling donor can proceed to a haplo-BMT. Patients with an HLA-matched related donor will proceed to a matched BMT.
  • Age 1-70 years
  • Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
  • Patients and donors must be able to sign consent forms. First degree relative should be willing to donate
  • Patients must be geographically accessible and willing to participate in all stages of treatment.
  • Eligible diagnoses: Patients with sickle cell anemia such as sickle cell anemia (Hb SS), Hb Sβ° thalassemia, Hb Sβ+thalassemia, Hb SC disease, Hb SE disease, Hb SD disease, Hemoglobin SO- Arab disease HbS with hereditary persistence of fetal hemoglobin. Other significant hemoglobinopathies.

Plus one of the following:

  • Attenuation of progressive disease (adults):
  • Severe and debilitating vaso-occlusive pain despite hydroxyurea or regular blood transfusion therapy.
  • Stroke and silent infarct; stroke or central nervous system event lasting more than 24 hours; MRI changes indicative of brain parenchyma damage and MRA evidence of cerebrovascular disease.
  • Recurrent acute chest syndrome requiring exchange hospitalization.
  • Chronic lung disease as defined by progressive restrictive disease irrespective of oxygen requirements.
  • Chronic kidney disease, CKD stage II - IV
  • Transfusion dépendent thalassemia

RECIPIENT EXCLUSION CRITERIA:

  • Poor performance status (ECOG>1).
  • Poor cardiac function: left ventricular ejection fraction<35%.
  • Poor pulmonary function: FEV1 and FVC<40% predicted.
  • Pulmonary hypertension moderate to severe by echocardiographic standards.
  • Poor liver function: direct bilirubin >3.1 mg/dl
  • HIV-positive
  • Minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available.
  • Prior transfusions from donor or recipient if caused alloimmunization vs. donor cells.
  • Women of childbearing potential who currently are pregnant (Beta-HCG+) or who are not practicing adequate contraception.
  • Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up. However, patients with history of stroke and significant cognitive deficit,that would preclude giving informed consent or assent will not be excluded, if they have a family member or significant other with Power of Attorney to also consent of their behalf.

CRITERIA FOR DONOR ELIGIBILITY:

  • Weight ≥ 20kg and age ≥ 18 years or per institutional guidelines
  • Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) and will be screened per the American Association of Blood Banks (AABB). (AABB guidelines and the recipients will be informed of any deviations.)
  • HLA-haploidentical first-degree relatives of the patient. Participants must be HLA typed at high resolution using DNA based typing at HLA-A, -B, -C and DRB1 and have available: An HLA haploidentical first degree relative donor (parents, siblings or half siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.

When more than one donor is available, the donor with the lowest number of HLA allele mismatches will be chosen, unless there is HLA cross-match incompatibility or a medical reason to select otherwise, in which case donor selection is the responsibility of the PI, in consultation with the immunogenetics laboratory. In cases where there is more than one donor with the least degree of mismatch, donors will be selected based on the most favorable combination of:

  • HLA compatibility in cross-match testing and
  • ABO compatibility
  • Donor age <40 years
  • Avoid female donors for male recipients and
  • Avoid CMV mismatched donor-recipient transplants:

HLA cross-matching (in order of priority):

  • Mutually compatible (no cross-matching antibodies)
  • Recipient non-cross-reactive with donor, donor cross-reactive with recipient
  • Mutually cross-reactive

ABO compatibility (in order of priority):

  • Compatible
  • Major incompatibility
  • Minor incompatibility
  • Major and minor incompatibility
  • Donors will be selected to minimize HLA mismatch in the Host-versus-graft direction.
  • Donors fulfilling the following criteria are ineligible for registration onto this study:
  • All donors will be screened by hemoglobin electrophoresis; donors with a clinically significant hemoglobinopathy are ineligible. Sickle trait is acceptable.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01850108
Other Study ID Numbers  ICMJE VICCNC BMT 12108
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Adetola A. Kassim, Vanderbilt-Ingram Cancer Center
Study Sponsor  ICMJE Vanderbilt-Ingram Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Adetola A Kassim, MD Vanderbilt-Ingram Cancer Center
PRS Account Vanderbilt-Ingram Cancer Center
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP