Reduced Intensity Conditioning in Patients Aged ≤35 With Non-Malignant Disorders Undergoing UCBT, BMT, or PBSCT (RIC HSCT NMD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2014 by 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: December 10, 2014
Last verified: December 2014
  Purpose

The objective of this study is to demonstrate the efficacy of using a reduced-intensity condition regimen with 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 HSCT. After transplant, subjects will be followed for late effects and for ongoing graft success.


Condition Intervention Phase
Primary Immunodeficiency Syndromes
Congenital Bone Marrow Failure Syndromes
Inherited Metabolic Disorders (IMD)
Hereditary Anemias
Patients With Sickle Disease Presenting Specific Symptoms
Drug: Hydroxyurea
Drug: Alemtuzumab
Drug: Fludarabine
Drug: Melphalan
Drug: Thiotepa
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
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:

Genetic and Rare Diseases Information Center resources: Adrenoleukodystrophy X-linked Adrenomyeloneuropathy Alpha-mannosidosis Type 1 Aplastic Anemia Autoimmune Lymphoproliferative Syndrome Bare Lymphocyte Syndrome Bare Lymphocyte Syndrome 2 Beta-thalassemia Chediak-Higashi Syndrome Chronic Granulomatous Disease Common Variable Immunodeficiency Congenital Amegakaryocytic Thrombocytopenia Diamond-Blackfan Anemia Dyskeratosis Congenita Dyskeratosis Congenita Autosomal Recessive Gaucher Disease Hemophagocytic Lymphohistiocytosis Hoyeraal Hreidarsson Syndrome Krabbe Leukodystrophy Leukodystrophy Metachromatic Leukodystrophy Mucopolysaccharidosis Mucopolysaccharidosis Type I Mucopolysaccharidosis Type II Mucopolysaccharidosis Type III Myelodysplastic Syndromes Omenn Syndrome Osteopetrosis Severe Combined Immunodeficiency Sickle Cell Anemia Thalassemia Wiskott Aldrich Syndrome
U.S. FDA Resources

Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Post-transplant treatment-related mortality (TRM) [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: No ]
    Assessment of post-transplant treatment-related mortality at day 100, day 180, and 1 year

  • Neurodevelopmental milestones [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Evaluation of the pace of attaining neurodevelopmental milestones after reduced-intensity conditioning as compared to myeloablative conditioning historical controls from the target population

  • Immune Reconstitution [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Evaluation of the pace of immune reconstitution

  • Severe opportunistic infections [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: Yes ]
    Evaluation of the incidence of severe opportunistic infections

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


Secondary Outcome Measures:
  • Donor cell engraftment [ Time Frame: 180 days post-transplant ] [ Designated as safety issue: No ]
    Determination of the feasibility of attaining robust donor cell engraftment (>50% donor chimerism at 180 days) following reduced-intensity conditioning (RIC) regimens prior to HSCT in the target population

  • Normal enzyme level [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population

  • Neutrophil recovery [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Determination of the pace of neutrophil recovery

  • Platelet recovery [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Determination of the pace of platelet recovery

  • Grade 3-4 organ toxicity [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Description of the incidence of grade 3-4 organ toxicity

  • Long-term complications [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Evaluation of the long-term complications such as sterility, endocrinopathy, and growth failure

  • Late graft failure [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: No ]
    Evaluation of the incidence of late graft failure


Estimated Enrollment: 30
Study Start Date: December 2013
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: STRATUM 1

STRATUM 1: Patients without immune deficiency and without recent history of CMV, adenovirus, RSV, Parainfluenza 3 infections. Patients with immune deficiency disorders but with an absolute lymphocyte count that is normal or near normal.

Patients in Stratum 1 will receive a full dose of alemtuzumab, and hydroxyurea, fludarabine, melphalan, and thiotepa.

Drug: Hydroxyurea
Hydroxyurea will be given orally at a single daily dose of 30 mg/kg
Other Names:
  • hydroxycarbamide
  • Hydrea
  • Droxia
Drug: Alemtuzumab
Alemtuzumab will be given IV per current institutional guidelines. A test dose will be given prior to conditioning. The treatment dose of alemtuzumab will be given during conditioning based on the patients' assigned stratum. Pre-medications for alemtuzumab include acetaminophen, diphenhydramine, and methylprednisolone on the day of alemtuzumab administration. Diphenhydramine, epinephrine, and methylprednisolone will be available at the bedside during administration of alemtuzumab. If the patient has a fever >38.5 C during or after alemtuzumab infusion, blood cultures will be drawn and antibiotic coverage will be added.
Other Name: Campath
Drug: Fludarabine
Fludarabine will be given IV at a dose of 30 mg/m2/dose (or 1 mg/kg/dose, whichever is lower) daily x5 doses
Other Name: Fludara
Drug: Melphalan
Melphalan will be given IV at a dose of 70 mg/m2/dose daily x2 doses.
Other Names:
  • Melphalan hydrochloride
  • Alkeran
Drug: Thiotepa
Thiotepa will be given IV at a dose of 200 mg/m2 x1 dose.
Other Name: ThioTEPA
Experimental: STRATUM 2

STRATUM 2: Patients with moderate lymphopenia, or patients without lymphopenia, nevertheless with recent history of CMV, adenovirus, RSV, Parainfluenza 3 infections.

Patients in Stratum 2 will receive a half dose of alemtuzumab, and hydroxyurea, fludarabine, melphalan, and thiotepa.

Drug: Hydroxyurea
Hydroxyurea will be given orally at a single daily dose of 30 mg/kg
Other Names:
  • hydroxycarbamide
  • Hydrea
  • Droxia
Drug: Alemtuzumab
Alemtuzumab will be given IV per current institutional guidelines. A test dose will be given prior to conditioning. The treatment dose of alemtuzumab will be given during conditioning based on the patients' assigned stratum. Pre-medications for alemtuzumab include acetaminophen, diphenhydramine, and methylprednisolone on the day of alemtuzumab administration. Diphenhydramine, epinephrine, and methylprednisolone will be available at the bedside during administration of alemtuzumab. If the patient has a fever >38.5 C during or after alemtuzumab infusion, blood cultures will be drawn and antibiotic coverage will be added.
Other Name: Campath
Drug: Fludarabine
Fludarabine will be given IV at a dose of 30 mg/m2/dose (or 1 mg/kg/dose, whichever is lower) daily x5 doses
Other Name: Fludara
Drug: Melphalan
Melphalan will be given IV at a dose of 70 mg/m2/dose daily x2 doses.
Other Names:
  • Melphalan hydrochloride
  • Alkeran
Drug: Thiotepa
Thiotepa will be given IV at a dose of 200 mg/m2 x1 dose.
Other Name: ThioTEPA
Experimental: STRATUM 3

STRATUM 3: Patients with severe lymphopenia

Patients in Stratum 3 will receive a test dose only of alemtuzumab, and hydroxyurea, fludarabine, melphalan, and thiotepa.

Drug: Hydroxyurea
Hydroxyurea will be given orally at a single daily dose of 30 mg/kg
Other Names:
  • hydroxycarbamide
  • Hydrea
  • Droxia
Drug: Alemtuzumab
Alemtuzumab will be given IV per current institutional guidelines. A test dose will be given prior to conditioning. The treatment dose of alemtuzumab will be given during conditioning based on the patients' assigned stratum. Pre-medications for alemtuzumab include acetaminophen, diphenhydramine, and methylprednisolone on the day of alemtuzumab administration. Diphenhydramine, epinephrine, and methylprednisolone will be available at the bedside during administration of alemtuzumab. If the patient has a fever >38.5 C during or after alemtuzumab infusion, blood cultures will be drawn and antibiotic coverage will be added.
Other Name: Campath
Drug: Fludarabine
Fludarabine will be given IV at a dose of 30 mg/m2/dose (or 1 mg/kg/dose, whichever is lower) daily x5 doses
Other Name: Fludara
Drug: Melphalan
Melphalan will be given IV at a dose of 70 mg/m2/dose daily x2 doses.
Other Names:
  • Melphalan hydrochloride
  • Alkeran
Drug: Thiotepa
Thiotepa will be given IV at a dose of 200 mg/m2 x1 dose.
Other Name: ThioTEPA

Detailed Description:

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many pediatric malignant and non-malignant disorders (NMD), the latter of which includes primary immunodeficiencies (PID), hemoglobinopathies, inherited metabolic disorders, and bone marrow failure syndromes. These NMD often have significant morbidity and risk for premature mortality, and HSCT can be curative by either replacement of defective hematopoietic cells with healthy donor cells or by the production of deficient enzyme by donor cells. HSCT in patients with NMD differs from that in malignant disorders for two important reasons- first, that these patients are typically naïve to chemotherapy and immunosuppression potentially leading to difficulties with engraftment, and second, that in the absence of malignancy, reduced-intensity conditioning (RIC) with subsequent bone marrow chimerism may be curative and result in decreased transplant-related mortality (TRM).

In this research study, instead of using the standard myeloablative conditioning, the study doctor is using reduced-intensity conditioning (RIC), in which lower doses of chemotherapy will be used. Although the lower doses may not eradicate every single stem cell in the bone marrow, nevertheless in the presented combination it still intends to eliminate already formed immune cells, paving the way to successful engraftment of donor cord blood cells. Engrafting cord blood cells can outcompete and reject the patients' few surviving stem cells. With reduced-intensity conditioning, the side effects on brain, heart, lung, liver, and other organ functions are usually less severe, and the patients can have a better long-term recovery. There is also realistic hope that after lower doses of chemotherapy many patients will avoid becoming sterile.

The purpose of this study is to collect data from the patients undergoing reduced-intensity conditioning before HSCT, so that the study doctor can compare it to the standard myeloablative conditioning with the expectation that there will be full therapeutic benefits paired with better survival rate and improved quality of life following the reduced intensity approach compared to myeloablative regimen.

The subjects will be stratified according to type of primary disease and degree of immune competence each of the three strata will use a different amount of alemtuzumab prior to transplant.

Male and female subjects aged 2 months to 35 years (inclusive) who meet all of the eligibility criteria will be considered for this study. Non-malignant disease populations amenable to stem cell treatment, listed in the eligibility section, will be considered appropriate for this study. A full list of eligibility criteria appears later in this record.

  Eligibility

Ages Eligible for Study:   2 Months to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient must be 2 months to 35 years (inclusive) of age for all diagnoses.
  2. Patients must have 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 107 cells/kg, or double unit grafts, each cord blood unit delivering at least 2x10e7 cells/kg.
  3. Patients must have an 8 of 8 or 7 of 8 HLA allele level matched unrelated donor bone marrow or peripheral blood progenitor graft
  4. Patient must have adequate function of other organ systems 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 normal.
    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 function 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.
  5. Patient, parent, or legal guardian must have given written informed consent and/or assent according to FDA guidelines.
  6. Patients may not be pregnant or lactating and must have a current negative pregnancy test if pubertal and/or menstruating.
  7. Patients must have a minimum life expectancy of at least 6 months.
  8. Patients must be HIV negative.
  9. Patients must not have uncontrolled infections at the time of cytoreduction.
  10. Patients should have a non-malignant disorder amenable to treatment by stem cell transplantation, including but not limited to:

    A. 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

    B. Congenital bone marrow failure syndromes including but not limited to:

    • Dyskeratosis Congenita (DC)

    • Congenital Amegakaryocytic Thrombocytopenia (CAMT)
    • Osteopetrosis

    C. Inherited Metabolic Disorders (IMD) including but not limited to:

    • Mucopolysaccharidoses o Hurler syndrome (MPS I)

      o Hunter syndrome (MPS II)

      o Sanfilippo syndrome (MPS II)

    • Leukodystrophies

      o Krabbe Disease, also known as globoid cell leukodystrophy

      o Metachromatic leukodystrophy (MLD)

      o X-linked adrenoleukodystrophy (ALD)

    • Other inherited metabolic disorders o alpha mannosidosis o Gaucher Disease
    • Other inheritable metabolic diseases where hematopoietic stem cell transplantation may be beneficial.

    D. Hereditary anemias

    • Thalassemia major

    • Sickle cell disease (SCD)

    • Diamond Blackfan Anemia (DBA)

    • other congenital transfusion dependent anemias

    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

    Exclusion Criteria:

1. No suitable unrelated donor graft choice as detailed above.

2. Available HLA-matched related living donor unaffected with recipient's disease and able and eligible to donate without previous UCB donation.

3. Allogeneic hematopoietic stem cell transplant within the previous 6 months.

4. Any active malignancy or MDS.

5. Severe acquired aplastic anemia.

7. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression of clinical symptoms).

8. Pregnancy or nursing mother.

9. HIV positive

10. Poorly controlled pulmonary hypertension.

11. 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: Mark Vander Lugt, MD 412-692-5427 mark.vanderlugt@chp.edu

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Natalie Cercone, RN    412-692-5004    natalie.cercone@chp.edu   
Sub-Investigator: Mark Vander Lugt, MD         
Sub-Investigator: Maria Escolar, MD         
Sub-Investigator: Rakesh Goyal, MD         
Sub-Investigator: Randy Windreich, MD         
Sub-Investigator: Michele Poe, PhD         
Principal Investigator: Paul Szabolcs, MD         
Sub-Investigator: Xiaohua Chen, PhD         
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Paul Szabolcs, MD University of Pittsburgh
  More Information

No publications provided

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: RIC for HSCT in NMD, PRO13100018
Study First Received: October 10, 2013
Last Updated: December 10, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pittsburgh:
Osteopetrosis
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 HSCT may be beneficial
Dyskeratosis Congenita (DC)
Congenital Amegakaryocytic Thrombocytopenia (CAMT)
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
Other inheritable metabolic diseases where HSCT may be beneficial.
Thalassemia major

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

ClinicalTrials.gov processed this record on May 27, 2015