Non-Myeloablative Conditioning and Bone Marrow Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Vanderbilt-Ingram Cancer Center
Sponsor:
Information provided by (Responsible Party):
Adetola A. Kassim, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT01850108
First received: May 1, 2013
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Sickle Cell Disease
Hemoglobinopathies
Drug: Thymoglobulin
Drug: Fludarabine
Drug: Cyclophosphamide (CTX)
Drug: Mesna
Drug: Sirolimus
Drug: Mycophenolate mofetil (MMF)
Procedure: Bone marrow transplantation
Radiation: Total body irradiation
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Disease and Other Hemoglobinopathies

Resource links provided by NLM:


Further study details as provided by Vanderbilt-Ingram Cancer Center:

Primary Outcome Measures:
  • Transplant-related mortality (TRM) [ Time Frame: at 1 year after BMT ] [ Designated as safety issue: No ]
    Defined as death in the absence of recurrent sickle cell disease or hemoglobinopathy


Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: Yes ]

    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


Estimated Enrollment: 8
Study Start Date: May 2013
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Non-Myeloablative Conditioning and Bone Marrow Transplantation 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

  Eligibility

Ages Eligible for Study:   2 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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 2-70 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 that also fulfill criterion from below.

Plus one of the following:

  1. Stroke or central nervous system event lasting more than 24 hours.
  2. MRI changes indicative of brain parenchyma damage.
  3. MRA evidence of cerebrovascular disease.
  4. Acute chest syndrome requiring exchange transfusion or hospitalization.
  5. Recurrent vaso-occlusive pain episodes and hospitalization crisis (more than 2/year for the last 2 years).
  6. Stage I or II sickle lung disease.
  7. Transfusion dependent thalassemia

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.

Criteria for donor eligibility

  • Weight ≥ 20kg and age ≥ 18 years
  • 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.)
  • 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 (i) HLA compatibility in cross-match testing and (ii) ABO compatibility:
  • HLA crossmatching (in order of priority)

    1. Mutually compatible (no cross-matching antibodies)
    2. Recipient non-cross-reactive with donor, donor cross-reactive with recipient
    3. 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.
  • Donor must have a hemoglobin S =/< ~50%.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01850108

Contacts
Contact: Vanderbilt-Ingram Clinical Trials Information Program 800-811-8480

Locations
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Clinical Trials Information Program    800-811-8480      
Principal Investigator: Adetola A Kassim, MD         
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
Investigators
Principal Investigator: Adetola A Kassim, MD Vanderbilt-Ingram Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Adetola A. Kassim, Associate Professor of Medicine; Clinical Director, Sickle Cell Anemia Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT01850108     History of Changes
Other Study ID Numbers: VICCNC BMT 12108
Study First Received: May 1, 2013
Last Updated: July 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Anemia, Sickle Cell
Hemoglobinopathies
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Cyclophosphamide
Mycophenolate mofetil
Mycophenolic Acid
Alkylating Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014