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

This study is currently recruiting participants.
Verified July 2017 by Fred Hutchinson Cancer Research Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT00919503
First Posted: June 12, 2009
Last Update Posted: July 21, 2017
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
medac GmbH
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
  Purpose
This phase II clinical trial studies how well treosulfan and fludarabine phosphate with or without low dose radiation before donor stem cell transplantation works in treating 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 are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan and fludarabine phosphate) with or without low dose radiation results in new blood-forming cells (engraftment) of the new donor cells without increased toxicities in patients with nonmalignant (noncancerous) diseases.

Condition Intervention Phase
Non-Malignant Procedure: Allogeneic Bone Marrow Transplantation Biological: Anti-Thymocyte Globulin Drug: Cyclosporine Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Methotrexate Drug: Mycophenolate Mofetil Procedure: Peripheral Blood Stem Cell Transplantation Drug: Tacrolimus Radiation: Total-Body Irradiation Drug: Treosulfan Procedure: Umbilical Cord Blood Transplantation Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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 [ Time Frame: 1 year following transplant ]
    Defined by engraftment of a regimen consisting of treosulfan and fludarabine phosphate followed by allogeneic hematopoietic cell transplantation in patients with nonmalignant inherited disorders.


Secondary Outcome Measures:
  • Disease response following hematopoietic cell transplantation [ Time Frame: Up to 5 years ]
    Will be assessed.

  • Donor chimerism [ Time Frame: Up to 5 years ]
    Peripheral blood chimerism for CD3, CD33, CD19, and CD56 will be evaluated.

  • Immune reconstitution following hematopoietic cell transplantation [ Time Frame: Up to 5 years ]
    Measured using samples of peripheral blood, and bone marrow aspirate.

  • Incidence of chronic graft-versus-host disease [ Time Frame: Within the two years (on average) following transplant ]
    Defined as those patients requiring systemic immunosuppression.

  • Incidence of grade II-IV acute graft-versus-host disease [ Time Frame: Within the first year following transplant ]
    Will be monitored.

  • Incidence of infections [ Time Frame: Within the first year following transplant ]
    Will be monitored.

  • Non-relapse mortality [ Time Frame: Up to 1 year following transplant ]
    Will be monitored in all patients.

  • Overall survival [ Time Frame: Within the two years following transplant ]
    Will be monitored.


Estimated Enrollment: 120
Actual Study Start Date: July 31, 2009
Estimated Primary Completion Date: February 1, 2018 (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.
Procedure: Allogeneic Bone Marrow Transplantation
Infused IV
Other Names:
  • Allo BMT
  • Allogeneic BMT
Biological: Anti-Thymocyte Globulin
Given IV
Other Names:
  • Antithymocyte Globulin
  • Antithymocyte Serum
  • ATG
  • ATGAM
  • ATS
  • Thymoglobulin
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039
Procedure: Peripheral Blood Stem Cell Transplantation
Infused IV
Other Names:
  • PBPC transplantation
  • PBSCT
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplant
  • Peripheral Stem Cell Transplantation
Drug: Tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic
Drug: Treosulfan
Given IV
Other Names:
  • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon
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.
Biological: Anti-Thymocyte Globulin
Given IV
Other Names:
  • Antithymocyte Globulin
  • Antithymocyte Serum
  • ATG
  • ATGAM
  • ATS
  • Thymoglobulin
Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Gengraf
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
Radiation: Total-Body Irradiation
Undergo total body irradiation
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation
Drug: Treosulfan
Given IV
Other Names:
  • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon
Procedure: Umbilical Cord Blood Transplantation
Single or double unit umbilical cord blood transplant, infused IV
Other Names:
  • Cord Blood Transplantation
  • UCB transplantation

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 transplant (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 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 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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   up to 49 Years   (Child, Adult)
Sexes Eligible for Study:   All
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 or as clinically indicated or following discussion with the PI
  • DONOR: HLA-matched sibling bone marrow in combination with HLA-matched sibling umbilical cord blood if the HLA-matched sibling umbilical cord blood was collected and stored; the HLA-matched sibling bone marrow and cord blood would be matched for HLA-A, B, C, DRB1, and DQB1
  • DONOR: Unrelated 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: Unrelated 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: Unrelated Umbilical Cord Blood: Selection of two umbilical cord blood (UCB) units is allowed to provide sufficient cell dose
  • DONOR: Unrelated Umbilical Cord Blood: The UCB unit with the least HLA disparity (with the patient) will be selected first (i.e., selection priority is 6/6 match > 5/6 match> 4/6 match); additional UCB units then may be selected to achieve the required cell dose; if a second unit is required, this unit will be the unit that most closely HLA matches the patient and meets minimum size criteria outlined below of at least 1.5 x 10^7 TNC/kg (ie a smaller more closely matched unit will be selected over a larger less well matched unit as long as minimum criteria are met)
  • DONOR: Unrelated Umbilical Cord Blood: Each UCB unit MUST contain at least 1.5 x 10^7 TNC per kilogram recipient weight
  • DONOR: Unrelated Umbilical Cord Blood: The total cell dose of the combined units must be at least 3.0 x 10^7 TNC per kilogram recipient weight

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 > 2 x 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 positive 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) unless approved by the PI
  • 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
  • DONOR: HLA-matched sibling cord blood exclusions: Any cord blood units without full maternal testing and negative results for hepatitis A, B, C, HIV, and HTLV-1 viruses; any additional available virology results on the unit itself will be reviewed but are not mandated, complete or always available; cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
  • DONOR: Unrelated Umbilical Cord Blood: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight
  • DONOR: Unrelated Umbilical Cord Blood: Any cord blood units without full maternal testing and negative results for hepatitis A, B, C, HIV, and HTLV-1 viruses; any additional available virology results on the unit itself will be reviewed but are not mandated, complete or always available; cord blood units are presumed to be CMV negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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 Completed
Portland, Oregon, United States, 97239
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Active, not recruiting
Nashville, Tennessee, United States, 37232
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Lauri M. Burroughs    206-667-2396    lburroug@fhcrc.org   
Principal Investigator: Lauri M. Burroughs         
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Lauri M. Burroughs    206-667-2396    lburroug@fhcrc.org   
Principal Investigator: Lauri M. Burroughs         
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Julie-An M. Talano    414-955-4170    jtalano@mcw.edu   
Principal Investigator: Julie-An M. Talano         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
medac GmbH
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Lauri Burroughs Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00919503     History of Changes
Other Study ID Numbers: 2256.00
NCI-2010-01277 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2256.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Submitted: June 11, 2009
First Posted: June 12, 2009
Last Update Posted: July 21, 2017
Last Verified: July 2017

Keywords provided by Fred Hutchinson Cancer Research Center:
hemophagocytic lymphohistiocytosis
nonmalignant diseases
nonmalignant inherited disorders
primary immunodeficiency diseases
primary immune deficiency disorders
chronic granulomatous
disease
IPEX syndrome
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:
Methotrexate
Fludarabine phosphate
Cyclosporine
Tacrolimus
Cyclosporins
Mycophenolic Acid
Thymoglobulin
Antilymphocyte Serum
Busulfan
Vidarabine
Fludarabine
Treosulfan
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Calcineurin Inhibitors
Antifungal Agents
Anti-Infective Agents