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 2015 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 8, 2015
Last verified: June 2015

June 11, 2009
June 8, 2015
July 2009
July 2017   (final data collection date for primary outcome measure)
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 ]
Engraftment [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00919503 on ClinicalTrials.gov Archive Site
  • Disease response following HCT [ Time Frame: Up to 5 years ] [ 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.
  • 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 chronic GVHD [ Time Frame: Within the two years (on average) 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 infections [ Time Frame: Within the first year following transplant ] [ Designated as safety issue: No ]
  • Non-relapse mortality [ Time Frame: Up to 1 year following transplant ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Within the two years following transplant ] [ Designated as safety issue: No ]
  • Incidence of non-relapse mortality at 200 days and at 1 year after transplant [ Designated as safety issue: No ]
  • Incidence of grade II-IV acute graft-versus-host disease (GVHD) [ Designated as safety issue: No ]
  • Incidence of chronic GVHD [ Designated as safety issue: No ]
  • Donor chimerism at 28 days and at 100 days after transplant [ Designated as safety issue: No ]
  • Disease response [ Designated as safety issue: No ]
  • Immune reconstitution [ Designated as safety issue: No ]
  • Incidence of infections [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Treosulfan and Fludarabine Phosphate Before Donor Stem Cell Transplant in Treating Patients With Nonmalignant Inherited Disorders
Allogeneic Hematopoietic Cell Transplantation for Patients With Nonmalignant Inherited Disorders Using a Treosulfan Based Preparative Regimen

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.

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 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.

Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Non-Malignant
  • Procedure: Allogeneic Bone Marrow Transplantation
    Infused IV
    Other Names:
    • Allo BMT
    • Allogeneic BMT
    • allogeneic bone marrow transplantation
  • 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
    • CYCLOSPORINE
    • 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
    • FLUDARABINE PHOSPHATE
    • Oforta
    • 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
    • Methotrexate LPF
    • Methotrexate Methylaminopterin
    • Methotrexatum
    • Metotrexato
    • Metrotex
    • Mexate
    • Mexate-AQ
    • MTX
    • Novatrex
    • Rheumatrex
    • Texate
    • Tremetex
    • Trexeron
    • Trixilem
    • WR-19039
  • Drug: Mycophenolate Mofetil
    Given IV or PO
    Other Names:
    • Cellcept
    • MMF
    • MYCOPHENOLATE MOFETIL
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Infused IV
    Other Names:
    • PBPC transplantation
    • Peripheral Blood Progenitor Cell Transplantation
    • Peripheral Stem Cell Support
    • Peripheral Stem Cell Transplantation
  • Drug: Tacrolimus
    Given IV or PO
    Other Names:
    • FK 506
    • Fujimycin
    • Prograf
    • Protopic
    • TACROLIMUS
  • Radiation: Total-Body Irradiation
    Undergo total body irradiation
    Other Names:
    • TOTAL BODY IRRADIATION
    • 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
    • TREOSULFAN
    • Treosulphan
    • Tresulfon
  • Procedure: Umbilical Cord Blood Transplantation
    Single or double unit umbilical cord blood transplant, infused IV
    Other Names:
    • Cord Blood Transplantation
    • UCB transplantation
    • umbilical cord blood transplantation
  • 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.
    Interventions:
    • Procedure: Allogeneic Bone Marrow Transplantation
    • Biological: Anti-Thymocyte Globulin
    • Drug: Fludarabine Phosphate
    • Other: Laboratory Biomarker Analysis
    • Drug: Methotrexate
    • Procedure: Peripheral Blood Stem Cell Transplantation
    • Drug: Tacrolimus
    • Drug: Treosulfan
  • 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.
    Interventions:
    • Biological: Anti-Thymocyte Globulin
    • Drug: Cyclosporine
    • Drug: Fludarabine Phosphate
    • Other: Laboratory Biomarker Analysis
    • Drug: Mycophenolate Mofetil
    • Radiation: Total-Body Irradiation
    • Drug: Treosulfan
    • Procedure: Umbilical Cord Blood Transplantation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
68
Not Provided
July 2017   (final data collection date for primary outcome measure)

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
  • 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 > 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)
  • 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: Umbilical Cord Blood: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight
  • DONOR: Umbilical Cord Blood: Any cord blood units without full maternal testing and negative results for hepatitis A, B, C, HIV, and human T-cell lymphotropic virus 1 (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
Both
up to 54 Years
No
United States
 
NCT00919503
2256.00, NCI-2010-01277, 2256.00, P30CA015704
Yes
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
  • medac GmbH
  • National Cancer Institute (NCI)
  • National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Lauri Burroughs Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP