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

NCT00919503 | Completed Phase 2 Results DMC FDA Drug

• 4 other identifiers: 2256.00NCI-2010-01277P30CA015704RG2809001
• Study Type: interventional
• Target: 98
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Non-Neoplastic Hematologic and Lymphocytic Disorder

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Preliminary Efficacy

  Number of patients engrafted (\>5% donor CD3+ peripheral blood chimerisms) at 1 year following transplant

  1 year following transplant

Secondary Outcomes (9)

• Non-relapse Mortality

  1 year following transplant

• Number of Patients With Grade II-IV Acute Graft-versus-host Disease

  Day 100 post transplant

• Number of Patients With of Chronic Graft-versus-host Disease

  1 year following transplant

• Donor Chimerism CD3 at 100 Days Post Transplant

  Day 100 post transplant

• Disease Response at One Year Following Hematopoietic Cell Transplantation

  1 year following transplant

Study Arms (2)

Regimen A (PBSCT and BMT)

EXPERIMENTAL

CONDITIONING REGIMEN A : Patients receive treosulfan IV on days -6 to -4 and fludarabine phosphate IV on days -6 to -2. Patients receive anti-thymocyte globulin IV 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. 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; Biological: Anti-Thymocyte Globulin; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Methotrexate; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Drug: Treosulfan

Regimen B (UBCT)

EXPERIMENTAL

CONDITIONING REGIMEN B: Patients receive treosulfan IV on days -6 to -4 and fludarabine phosphate IV on days -6 to -2. Patients receive anti-thymocyte globulin IV 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. 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; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Radiation: Total-Body Irradiation; Drug: Treosulfan; Procedure: Umbilical Cord Blood Transplantation

Interventions

Allogeneic Bone Marrow Transplantation PROCEDURE

Infused IV

Also known as: Allo BMT, Allogeneic BMT

Regimen A (PBSCT and BMT)

Anti-Thymocyte Globulin BIOLOGICAL

Given IV

Also known as: Antithymocyte Globulin, Antithymocyte Serum, ATG, ATGAM, ATS, Thymoglobulin

Regimen A (PBSCT and BMT); Regimen B (UBCT)

Cyclosporine DRUG

Given IV or PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Regimen B (UBCT)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Regimen A (PBSCT and BMT); Regimen B (UBCT)

Laboratory Biomarker Analysis OTHER

Correlative studies

Regimen A (PBSCT and BMT); Regimen B (UBCT)

Methotrexate DRUG

Given IV

Also known as: 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

Regimen A (PBSCT and BMT)

Mycophenolate Mofetil DRUG

Given IV or PO

Also known as: Cellcept, MMF

Regimen B (UBCT)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Infused IV

Also known as: PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation

Regimen A (PBSCT and BMT)

Tacrolimus DRUG

Given IV or PO

Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic

Regimen A (PBSCT and BMT)

Total-Body Irradiation RADIATION

Undergo total body irradiation

Also known as: Total Body Irradiation, Whole-Body Irradiation

Regimen B (UBCT)

Treosulfan DRUG

Given IV

Also known as: 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-, Dihydroxybusulfan, Ovastat, Treosulphan, Tresulfon

Regimen A (PBSCT and BMT); Regimen B (UBCT)

Umbilical Cord Blood Transplantation PROCEDURE

Single or double unit umbilical cord blood transplant, infused IV

Also known as: Cord Blood Transplantation, UCB transplantation

Regimen B (UBCT)

Eligibility Criteria

• Age: Up to 49 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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: PBSC is the preferred cell source (when feasible) for fully matched donors; PBSC may also be used for a mismatched donor following discussion with the PI; bone marrow is allowed when PBSC is not feasible or as determined by 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 (i.e. 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

You may not qualify if:

• 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: Unrelated Umbilical Cord Blood: Any cord blood units with \< 1.5 x 10\^7 total nucleated cells per kilogram recipient weight

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• medac GmbH: collaborator
• National Cancer Institute (NCI): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (6)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Primary Immunodeficiency Diseases; Disease; Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome; Lymphohistiocytosis, Hemophagocytic; Wiskott-Aldrich Syndrome; Bone Marrow Failure Disorders; Shwachman-Diamond Syndrome; Dyskeratosis Congenita; Anemia, Diamond-Blackfan; Metabolism, Inborn Errors; Metabolic Diseases; Hemoglobinopathies; Anemia, Sickle Cell; Thalassemia

Interventions

Antilymphocyte Serum; thymoglobulin; Cyclosporine; Cyclosporins; fludarabine phosphate; Methotrexate; merphos; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Tacrolimus; Whole-Body Irradiation; treosulfan; Cord Blood Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Lymphopenia; Leukopenia; Cytopenia; Hemorrhagic Disorders; Leukocyte Disorders; Genetic Diseases, X-Linked; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Pancreatic Diseases; Digestive System Diseases; Congenital Bone Marrow Failure Syndromes; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Nutritional and Metabolic Diseases; Lipomatosis; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Red-Cell Aplasia, Pure; Anemia, Hemolytic, Congenital; Anemia, Hemolytic

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Macrolides; Lactones; Radiotherapy; Investigative Techniques

Results Point of Contact

• Title: Dr. Lauri Burroughs
• Organization: Fred Hutchinson Cancer Research Center

lburroug@fredhutch.org

206-667-2396

Study Officials

• Lauri M. Burroughs

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Clinical Research Division, Fred Hutch; Director, Non-Malignant Transplant Program

Study Record Dates

• First Submitted: June 11, 2009
• First Posted: June 12, 2009
• Study Start: July 31, 2009
• Primary Completion: June 10, 2020
• Study Completion: June 10, 2020
• Last Updated: August 13, 2021
• Results First Posted: August 13, 2021

Record last verified: 2021-07

Locations

US (6)