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Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Paul Szabolcs, University of Pittsburgh
Sponsor:
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01962415
First received: October 10, 2013
Last updated: June 2, 2017
Last verified: June 2017
  Purpose
The objective of this study is to evaluate the efficacy of using a reduced-intensity condition (RIC) regimen with umbilical cord blood transplant (UCBT), double cord UCBT, matched unrelated donor (MUD) bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) in patients with non-malignant disorders that are amenable to treatment with hematopoietic stem cell transplant (HSCT). After transplant, subjects will be followed for late effects and for ongoing graft success.

Condition Intervention Phase
Primary Immunodeficiency (PID) Congenital Bone Marrow Failure Syndromes Inherited Metabolic Disorders (IMD) Hereditary Anemias Inflammatory Conditions Drug: Hydroxyurea Drug: Alemtuzumab Drug: Fludarabine Drug: Melphalan Drug: Thiotepa Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase II Study of Reduced Intensity Conditioning in Patients ≤35 Years of Age With Non-Malignant Disorders Undergoing Umbilical Cord Blood, Bone Marrow, or Peripheral Blood Stem Cell Transplantation Transplantation

Resource links provided by NLM:


Further study details as provided by Paul Szabolcs, University of Pittsburgh:

Primary Outcome Measures:
  • Post-transplant treatment-related mortality (TRM) [ Time Frame: 1 year post-transplant ]
    The number of deaths related to the research intervention at day 100, 6 months, and 1 year post-transplant.

  • Neurodevelopmental milestones [ Time Frame: 2 years post-transplant ]
    Evaluation of the pace of attaining neurodevelopmental milestones after reduced-intensity conditioning as compared to myeloablative conditioning historical controls from the target population(s).

  • Immune Reconstitution [ Time Frame: 2 years post-transplant ]
    Evaluation of the pace of immune reconstitution.

  • Severe opportunistic infections [ Time Frame: 2 years post-transplant ]
    Evaluation of the incidence of severe opportunistic infections.

  • GVHD occurrence [ Time Frame: 2 years post-transplant ]
    Description of the incidence of acute GVHD (II-IV) and chronic extensive GVHD.


Secondary Outcome Measures:
  • Donor cell engraftment [ Time Frame: 6 months post-transplant ]
    Determination of the feasibility of attaining robust donor cell engraftment (>50% donor chimerism at 6 months) following reduced-intensity conditioning (RIC) regimens prior to HSCT in the target population(s).

  • Normal enzyme level [ Time Frame: 2 years post-transplant ]
    Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population(s).

  • Neutrophil recovery [ Time Frame: 2 years post-transplant ]
    Determination of the pace of neutrophil recovery.

  • Platelet recovery [ Time Frame: 2 years post-transplant ]
    Determination of the pace of platelet recovery.

  • Grade 3-4 organ toxicity [ Time Frame: 2 years post-transplant ]
    The number of grade 3-4 organ adverse events.

  • Long-term complications [ Time Frame: 2 years post-transplant ]
    Evaluation of the long-term complications such as sterility, endocrinopathy, and growth failure.

  • Late graft failure [ Time Frame: 2 years post-transplant ]
    Evaluation of the incidence of late graft failure.


Estimated Enrollment: 30
Actual Study Start Date: June 26, 2012
Estimated Study Completion Date: November 2019
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: UCBT:transfusion dependent anemias or increased rejection risk
Day -21 to -19: Alemtuzumab + Hydroxyurea; Day -18 to -10: Hydroxyurea; Day -9 to -5: Fludarabine + Hydroxyurea; Day -4 to -3: Melphalan; Day -2: Thiotepa; Day -1: Rest; Day 0: Transplant
Drug: Hydroxyurea
Oral administration at 30 mg/kg/day.
Other Names:
  • hydroxycarbamide
  • Hydrea
  • Droxia
Drug: Alemtuzumab

Intravenous (IV) administration. The first dose for each arm will be a test dose (0.2 mg/kg max 5 mg). The treatment doses of alemtuzumab will be based on the patients' assigned stratum as determined by their age, lymphocyte count and presence of infection.

Stratum 1: 1 mg/kg (max dose of 30 mg); Stratum 2: 0.5 mg/kg (max dose of 15 mg); Stratum 3: No treatment dose, test dose only.

Other Name: Campath
Drug: Fludarabine
IV administration at 30 mg/m2/day or 1 mg/kg/dose, whichever is lower.
Other Name: Fludara
Drug: Melphalan
IV administration at 70 mg/m2/dose.
Other Names:
  • Melphalan hydrochloride
  • Alkeran
Drug: Thiotepa
IV administration at 200 mg/m2/dose
Experimental: BMT, PBSCT and not transfusion dependent UCBT
Start of conditioning to Day -13: Alemtuzumab + Hydroxyurea; Day -12 to -10: Hydroxyurea; Day -9 to -5: Fludarabine + Hydroxyurea; Day -4 to -3: Melphalan; Day -2: Thiotepa; Day -1: Rest; Day 0: Transplant
Drug: Hydroxyurea
Oral administration at 30 mg/kg/day.
Other Names:
  • hydroxycarbamide
  • Hydrea
  • Droxia
Drug: Alemtuzumab

Intravenous (IV) administration. The first dose for each arm will be a test dose (0.2 mg/kg max 5 mg). The treatment doses of alemtuzumab will be based on the patients' assigned stratum as determined by their age, lymphocyte count and presence of infection.

Stratum 1: 1 mg/kg (max dose of 30 mg); Stratum 2: 0.5 mg/kg (max dose of 15 mg); Stratum 3: No treatment dose, test dose only.

Other Name: Campath
Drug: Fludarabine
IV administration at 30 mg/m2/day or 1 mg/kg/dose, whichever is lower.
Other Name: Fludara
Drug: Melphalan
IV administration at 70 mg/m2/dose.
Other Names:
  • Melphalan hydrochloride
  • Alkeran
Drug: Thiotepa
IV administration at 200 mg/m2/dose

Detailed Description:

For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies) a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage, as a result of the underlying disease, may remain present after the HSCT.

For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the main intent of the transplant is to slow down, or stop, the progress of the disease. In select few cases/diseases, the presence of healthy bone marrow derived cells may even prevent progression and prevent neurological decline.

In this research study, instead of using the standard myeloablative conditioning, the study doctor is using RIC, in which significantly lower doses of chemotherapy will be used. The lower doses may not eradicate every stem cell in the patient's bone marrow, however, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress, the patients' surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe and late toxic effects should also be reduced.

The purpose of this study is to collect data from the patients undergoing reduced-intensity conditioning before HSCT, and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with better survival rate, less organ toxicity and improved quality of life, following the RIC compared to the myeloablative regimen.

  Eligibility

Ages Eligible for Study:   2 Months to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion:

  1. A 4/6, 5/6 or 6/6 HLA matched related or unrelated UCB unit available that will deliver a pre-cryopreservation total nucleated cell dose of ≥ 3 x 10e7 cells/kg, or double unit grafts, each cord blood unit delivering at least 2 x 10e7 cells/kg OR an 8 of 8 or 7 of 8 HLA allele level matched unrelated donor bone marrow or peripheral blood progenitor graft.
  2. Adequate organ function as measured by:

    1. Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m2.
    2. Hepatic transaminases (ALT/AST) ≤ 4 x upper limit of normal (ULN).
    3. Adequate cardiac function by echocardiogram or radionuclide scan (shortening fraction > 26% or ejection fraction > 40% or > 80% of normal value for age).
    4. Pulmonary evaluation testing demonstrating CVC or FEV1/FVC of ≥ 50% of predicted for age and/or resting pulse oximeter ≥ 92% on room air or clearance by the pediatric or adult pulmonologist. For adult patients DLCO (corrected for hemoglobin) should be ≥ 50% of predicted if the DLCO can be obtained.
  3. Written informed consent and/or assent according to FDA guidelines.
  4. Negative pregnancy test if pubertal and/or menstruating.
  5. HIV negative.
  6. A non-malignant disorder amenable to treatment by stem cell transplantation, including but not limited to:

    1. Primary Immunodeficiency syndromes including but not limited to:

      • Severe Combined Immune Deficiency (SCID) with NK cell activity
      • Omenn Syndrome
      • Bare Lymphocyte Syndrome (BLS)
      • Combined Immune Deficiency (CID) syndromes
      • Combined Variable Immune Deficiency (CVID) syndrome
      • Wiskott-Aldrich Syndrome
      • Leukocyte adhesion deficiency
      • Chronic granulomatous disease (CGD)
      • X-linked Hyper IgM (XHIM) syndrome
      • IPEX syndrome
      • Chediak - Higashi Syndrome
      • Autoimmune Lymphoproliferative Syndrome (ALPS)
      • Hemophagocytic Lymphohistiocytosis (HLH) syndromes
      • Lymphocyte Signaling defects
      • Other primary immune defects where hematopoietic stem cell transplantation may be beneficial
    2. Congenital bone marrow failure syndromes including but not limited to:

      • Dyskeratosis Congenita (DC)
      • Congenital Amegakaryocytic Thrombocytopenia (CAMT)
      • Osteopetrosis
    3. Inherited Metabolic Disorders (IMD) including but not limited to:

      • Mucopolysaccharidoses

        • Hurler syndrome (MPS I)
        • Hunter syndrome (MPS II)
        • Sanfilippo syndrome (MPS II)
      • Leukodystrophies

        • Krabbe Disease, also known as globoid cell leukodystrophy
        • Metachromatic leukodystrophy (MLD)
        • X-linked adrenoleukodystrophy (ALD)
      • Other inherited metabolic disorders

        • alpha mannosidosis
        • Gaucher Disease
      • Other inheritable metabolic diseases where hematopoietic stem cell transplantation may be beneficial.
    4. Hereditary anemias

      • Thalassemia major
      • Sickle cell disease (SCD) - patients with sickle disease must have one or more of the following:

        • Overt or silent stroke
        • Pain crises ≥ 2 episodes per year for past year
        • One or more episodes of acute chest syndrome
        • Osteonecrosis involving ≥ 1 joints
        • Priapism
      • Diamond Blackfan Anemia (DBA)
      • Other congenital transfusion dependent anemias
    5. Inflammatory Conditions

      • Crohn's Disease/Inflammatory Bowel Disease

Exclusion:

  1. Allogeneic hematopoietic stem cell transplant within the previous 6 months.
  2. Any active malignancy or MDS.
  3. Severe acquired aplastic anemia.
  4. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression of clinical symptoms).
  5. Pregnancy or nursing mother.
  6. Poorly controlled pulmonary hypertension.
  7. Any condition that precludes serial follow-up.
  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: NCT01962415

Contacts
Contact: Paul Szabolcs, MD 412-692-5427 paul.szabolcs@chp.edu
Contact: Shawna McIntyre, BSN, RN 412-692-5552 mcintyresm@upmc.edu

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Shawna McIntyre, BSN, RN    412-692-5552    mcintyresm@upmc.edu   
Sub-Investigator: Maria Escolar, MD         
Sub-Investigator: Randy Windreich, MD         
Sub-Investigator: Xiaohua Chen, PhD         
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Paul Szabolcs, MD University of Pittsburgh
  More Information

Responsible Party: Paul Szabolcs, Chief, Division of Blood and Marrow Transplantation and Cellular Therapies, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01962415     History of Changes
Other Study ID Numbers: PRO13100018
Study First Received: October 10, 2013
Last Updated: June 2, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Paul Szabolcs, University of Pittsburgh:
Chronic granulomatous disease (CGD)
Severe Combined Immune Deficiency (SCID)
Omenn Syndrome
Bare Lymphocyte Syndrome (BLS)
Combined Immune Deficiency (CID) syndromes
Combined Variable Immune Deficiency (CVID) syndrome
Wiskott-Aldrich Syndrome
Leukocyte adhesion deficiency
X-linked Hyper IgM (XHIM) syndrome
IPEX syndrome
Chediak - Higashi Syndrome
Autoimmune Lymphoproliferative Syndrome (ALPS)
Hemophagocytic Lymphohistiocytosis (HLH) syndromes
Lymphocyte Signaling defects
Dyskeratosis Congenita (DC)
Congenital Amegakaryocytic Thrombocytopenia (CAMT)
Osteopetrosis
Mucopolysaccharidoses
Hurler syndrome (MPS I)
Hunter syndrome (MPS II)
Sanfilippo syndrome (MPS II)
Leukodystrophies
Krabbe Disease
Metachromatic leukodystrophy (MLD)
X-linked adrenoleukodystrophy (ALD)
Alpha mannosidosis
Gaucher Disease
Thalassemia major
Sickle cell disease (SCD)
Diamond Blackfan Anemia (DBA)

Additional relevant MeSH terms:
Disease
Syndrome
Anemia
Immunologic Deficiency Syndromes
Metabolic Diseases
Pancytopenia
Hemoglobinuria, Paroxysmal
Pathologic Processes
Hematologic Diseases
Immune System Diseases
Anemia, Hemolytic
Myelodysplastic Syndromes
Bone Marrow Diseases
Fludarabine
Fludarabine phosphate
Alemtuzumab
Melphalan
Hydroxyurea
Thiotepa
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antisickling Agents

ClinicalTrials.gov processed this record on July 25, 2017