Treosulfan and Fludarabine Phosphate Before Donor Stem Cell Transplant in Treating Patients With Nonmalignant Inherited Disorders

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
medac GmbH
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00919503
First received: June 11, 2009
Last updated: June 24, 2014
Last verified: June 2014
  Purpose

The purpose of this phase II clinical trial is to see if the combination of two chemotherapy drugs, treosulfan and fludarabine phosphate with or without low dose radiation, just prior to stem cell transplantation is safe and effective in patients with nonmalignant (noncancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (noncancerous) diseases such as primary immunodeficiency disorders, bone marrow failure syndromes, hemoglobinopathies, and inborn errors of metabolism (metabolic disorders). Powerful chemotherapy drugs and/or radiation are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy and/or radiation which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators at the Fred Hutchinson Cancer Research Center in collaboration with Oregon Health & Sciences University, Vanderbilt University, and Medical College of Wisconsin are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan and fludarabine phosphate) with or without low dose radiation results in engraftment of the new donor cells without increased toxicities in patients with nonmalignant (noncancerous) diseases.


Condition Intervention Phase
Nonmalignant Neoplasm
Drug: treosulfan
Drug: fludarabine phosphate
Biological: anti-thymocyte globulin
Radiation: total-body irradiation
Procedure: allogeneic bone marrow transplantation
Procedure: peripheral blood stem cell transplantation
Procedure: umbilical cord blood transplantation
Drug: tacrolimus
Drug: methotrexate
Drug: cyclosporine
Drug: mycophenolate mofetil
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Cell Transplantation for Patients With Nonmalignant Inherited Disorders Using a Treosulfan Based Preparative Regimen.

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Preliminary efficacy as defined by engraftment of a regimen consisting of treosulfan and fludarabine phosphate followed by allogeneic HCT in patients with nonmalignant inherited disorders [ Time Frame: 1 year following transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Non-relapse mortality [ Time Frame: Up to 1 year following transplant ] [ Designated as safety issue: No ]
  • Incidence of grade II-IV acute GVHD [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]
  • Incidence of chronic GVHD [ Time Frame: Within the two years (on average) following transplant ] [ Designated as safety issue: No ]
  • Donor chimerism [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Peripheral blood chimerism for CD3, CD33, CD19, and CD56 will be evaluated.

  • Disease response following HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Immune reconstitution following HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Measured using samples of peripheral blood, and bone marrow aspirate.

  • Incidence of infections [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Within the two years following transplant ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: July 2009
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group I (PBSCT and BMT)
See Detailed Description. Patients undergoing bone marrow or PBSC transplantation receive tacrolimus IV continuously or PO twice daily on days -1 to 50 followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Drug: treosulfan
Given IV
Other Names:
  • dihydroxybusulfan
  • Ovastat
  • tresulfon
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin
Procedure: allogeneic bone marrow transplantation
Infused IV
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Procedure: peripheral blood stem cell transplantation
Infused IV
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Drug: methotrexate
Given IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
Other: laboratory biomarker analysis
Correlative studies
Experimental: Group II (UBCT)
See Detailed Description. Patients undergoing UCB transplantation receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to 100 followed by a taper until day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil IV or PO every 8 hours on days 0 to 40 followed by a taper until day 96 in the absence of GVHD.
Drug: treosulfan
Given IV
Other Names:
  • dihydroxybusulfan
  • Ovastat
  • tresulfon
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin
Radiation: total-body irradiation
Undergo total body irradiation
Other Name: TBI
Procedure: umbilical cord blood transplantation
Single or double unit umbilical cord blood transplant, infused IV
Other Names:
  • cord blood transplantation
  • transplantation, umbilical cord blood
  • UCB transplantation
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate, within the limits of a phase II study, the preliminary efficacy, as defined by engraftment, of a regimen consisting of treosulfan and fludarabine (fludarabine phosphate) followed by allogeneic hematopoietic cell transplantation (HCT) in patients with nonmalignant inherited disorders.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of non-relapse mortality 200 days and 1 year post-HCT.

II. To evaluate the incidence of grade II-IV acute graft-versus-host disease (GVHD).

III. To evaluate the incidence of chronic GVHD as defined as those patients requiring systemic immunosuppression.

IV. To evaluate donor chimerism on days +28 and +100.

V. To assess disease response following HCT.

VI. To evaluate immune reconstitution following HCT.

VII. To evaluate the incidence of infections.

VIII. To evaluate overall survival.

OUTLINE:

CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 1 hour on days -6 to -2. Patients receive anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1.

TRANSPLANTATION: Patients will receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status.

IMMUNOSUPPRESSION: Patients will receive a combination of immunosuppressive medications to try and prevent graft-versus-host disease. If patients undergo bone marrow or PBSC transplantation, tacrolimus and methotrexate will be used. If patients undergo cord blood transplantation, cyclosporine and mycophenolate mofetil will be used. In general, patients will receive immunosuppression until at least 180 days after transplantation; however they could be on immunosuppression longer if they develop graft versus host disease.

After completion of study treatment, patients are followed up periodically for 5 years.

  Eligibility

Ages Eligible for Study:   up to 54 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a nonmalignant disease treatable by allogeneic HCT
  • Patients with a known nonmalignant disease that is not clearly defined will need to be discussed with the protocol principal investigator (PI) (Dr. Lauri Burroughs) and potentially the nonmalignant board to determine if they are eligible for HCT on this study
  • DONOR: Human leukocyte antigens (HLA)-identical related donors or unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 or mismatched for a single allele at HLA-A, B, C, DRB1 or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing
  • DONOR: Bone marrow is the preferred cell source; PBSC are allowed if donor refuses or is unable to give marrow
  • DONOR: Umbilical Cord Blood: Unit selection is based on the cryopreserved total nucleated cell (TNC) dose and matching at HLA-A, B antigen level and DRB1 allele level typing; while HLA-C antigen/allele level typing is not considered in the matching criteria, if available, may be used to optimize unit selection
  • DONOR: Umbilical Cord Blood: The patient and the cord blood unit(s) must be matched for at least 4 of 6 loci as defined above
  • DONOR: Umbilical Cord Blood: Selection of two UCB units is allowed to provide sufficient cell dose

Exclusion Criteria:

  • Patients with idiopathic aplastic anemia and Fanconi anemia; (patients with aplastic anemia associated with paroxysmal nocturnal hemoglobinuria [PNH] or inherited marrow failure syndromes, except Fanconi anemia, will be allowed)
  • Patients with impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
  • Patients with impaired pulmonary function as evidenced by diffusion capacity of the lung for carbon monoxide (DLCO) < 50% of predicted (or, if unable to perform pulmonary function tests, then oxygen [O2] saturation < 92% on room air)
  • Patients with impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2X upper normal limit or dialysis-dependent
  • Patients with evidence of synthetic dysfunction or severe cirrhosis requiring deferral of conditioning as recommended by a gastroenterology specialist
  • Patients with an active infectious disease requiring deferral of conditioning; as recommended by an infectious disease specialist
  • Patients who are seropositive for human immunodeficiency virus (HIV)
  • Females who are pregnant or breast-feeding
  • Patients with a known hypersensitivity to treosulfan and/or fludarabine
  • Receiving another experimental drug within 4 weeks of initiation of conditioning (day -6)
  • DONOR: Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
  • DONOR: HIV-positive
  • DONOR: With active infectious hepatitis
  • DONOR: Females with a positive pregnancy test
  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: NCT00919503

Locations
United States, Colorado
Children's Hospital Colorado Active, not recruiting
Aurora, Colorado, United States, 80045
United States, Oregon
Oregon Health and Science University Active, not recruiting
Portland, Oregon, United States, 97239
United States, Tennessee
Vanderbilt-Ingram Cancer Center Active, not recruiting
Nashville, Tennessee, United States, 37232
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Lauri M. Burroughs    206-667-2396      
Principal Investigator: Lauri M. Burroughs         
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53201
Contact: Julie-An M. Talano    414-955-4170      
Principal Investigator: Julie-An M. Talano         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
medac GmbH
Investigators
Principal Investigator: Lauri Burroughs Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00919503     History of Changes
Other Study ID Numbers: 2256.00, NCI-2010-01277, 2256.00, P30CA015704
Study First Received: June 11, 2009
Last Updated: June 24, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Fred Hutchinson Cancer Research Center:
nonmalignant diseases
nonmalignant inherited disorders
primary immunodeficiency diseases
primary immune deficiency disorders
chronic granulomatous
disease
IPEX syndrome
hemophagocytic lymphohistiocytosis
Wiskott Aldrich Syndrome
bone marrow failure syndromes
Shwachman Diamond Syndrome
Dyskeratosis Congenita
Diamond Blackfan Anemia
inborn errors of metabolism
metabolic diseases
hemoglobinopathies
sickle cell disease
thalassemia
reduced intensity transplantation
hematopoietic cell transplantation
bone marrow transplantation
umbilical cord blood transplantation

Additional relevant MeSH terms:
Antilymphocyte Serum
Cyclosporine
Cyclosporins
Fludarabine
Fludarabine phosphate
Methotrexate
Mycophenolate mofetil
Mycophenolic Acid
Tacrolimus
Treosulfan
Vidarabine
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on October 23, 2014