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

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Non-Malignant

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

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Lauri Burroughs, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

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.

Clinical Details

Official title: Allogeneic Hematopoietic Cell Transplantation for Patients With Nonmalignant Inherited Disorders Using a Treosulfan Based Preparative Regimen

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: 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

Secondary outcome:

Disease response following HCT

Donor chimerism

Immune reconstitution following HCT

Incidence of chronic GVHD

Incidence of grade II-IV acute GVHD

Incidence of infections

Non-relapse mortality

Overall survival

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 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

Minimum age: N/A. Maximum age: 54 Years. Gender(s): Both.

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

- 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

Locations and Contacts

Children's Hospital Colorado, Aurora, Colorado 80045, United States; Active, not recruiting

Oregon Health and Science University, Portland, Oregon 97239, United States; Completed

Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee 37232, United States; Active, not recruiting

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Lauri M. Burroughs, Phone: 206-667-2396
Lauri M. Burroughs, Principal Investigator

Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53201, United States; Recruiting
Julie-An M. Talano, Phone: 414-955-4170
Julie-An M. Talano, Principal Investigator

Additional Information

Starting date: July 2009
Last updated: June 8, 2015

Page last updated: August 20, 2015

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