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Blood Samples to Identify Biomarkers of Busulfan

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. Read our disclaimer for details. Identifier: NCT02291965
Recruitment Status : Active, not recruiting
First Posted : November 17, 2014
Last Update Posted : May 5, 2020
University of Washington
Seattle Children's Hospital
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:

Specific Aim 1: To determine whether endogenous metabolomics-based biomarkers obtained before IV BU administration can predict IV BU clearance.

Specific Aim 2: To characterize IV BU metabolism by metabolomics.

Specific Aim 3: To identify covariates influencing IV BU pharmacokinetics.

Condition or disease
Leukemia Lymphoma Multiple Myeloma Immunodeficiency Myelodysplastic Syndrome

Detailed Description:
The long-range goal of this work is to improve overall survival in hematopoietic stem cell transplant (HCT) recipients by personalizing their conditioning regimen and/or intravenous (IV) busulfan (BU) doses using metabolomics. BU is an essential part of the majority of HCT conditioning regimens, but has a narrow therapeutic index; low BU plasma exposure (caused by rapid clearance) is associated with an increased risk of rejection or relapse, while high BU plasma exposure is associated with an increased risk of hepatotoxicity. Although pharmacokinetic (PK)-based dosing to a target BU exposure is often conducted, relapse and toxicity continue to be problematic. Furthermore, shorter IV BU courses necessitate alternative methods to personalize IV BU. IV BU clearance, however, is not associated with polymorphisms of glutathione S-transferase (GST) A1 and GSTM1, the predominant GSTs in BU conjugation with glutathione. Therefore, investigators seek to test the working hypothesis that metabolomic signature, which provides novel insight into the in vivo cellular response and metabolite identification, is associated with IV BU clearance. Investigators will first determine if endogenous metabolomics-based biomarkers obtained before BU administration can predict IV BU clearance. Researchers will evaluate endogenous biomarkers using a targeted (glutathione pathway) and global analyses via liquid chromatography-mass spectroscopy. In addition, investigators seek to evaluate IV BU metabolism using metabolomics in parallel with gas chromatography-mass selective detection in patients receiving PK-based IV BU. Researchers will evaluate plasma concentrations of eight different metabolites, building upon their experience with tetrahydrothiophene (THT+). To complement this metabolomic work, investigators seek to validate covariates associated with IV BU PK, specifically age and body size, to mitigate a typical challenge for metabolomics research: the lack of understanding of potentially confounding factors. FHCRC has been a reference clinical laboratory for PK-based BU dosing since 1996 and thus, FHCRC researchers have the largest database of IV BU PK. Using population pharmacokinetic (popPK) analysis, investigators will validate covariates for IV BU PK to guide future metabolomic studies. This popPK analysis can immediately improve patient care by using covariates to more accurately estimate an IV BU starting dose (i.e., before PK-based dosing) and by creating a limited sampling schedule to more efficiently use PK-based dosing. These complementary aims, which seek to identify novel metabolomics-based biomarkers, could overcome a critical barrier to HCT conditioning of balancing between response and toxicity. Based on compelling preliminary data, researchers expect to identify an endogenous metabolomic signature that will influence the choice of an IV BU starting dose with the intention of improving overall survival for patients receiving IV BU-containing HCT regimens.

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Study Type : Observational
Actual Enrollment : 139 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Optimizing Busulfan: Efficacy, Toxicity, and Pharmacometabolomics
Actual Study Start Date : November 2014
Actual Primary Completion Date : April 20, 2019
Estimated Study Completion Date : May 31, 2023

Primary Outcome Measures :
  1. Busulfan clearance [ Time Frame: 24 hours after start of busulfan ]

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 1 year ]

Biospecimen Retention:   Samples Without DNA
Plasma samples from metabolomic and/or pharmacokinetic analysis.

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients receiving targeted IV busulfan as part of conditioning for a hematopoietic stem cell transplant

Inclusion Criteria:

  • Scheduled to receive targeted intravenous busulfan (any dose, any number of doses, any dosing frequency) as part of their hematopoietic stem cell transplant conditioning;
  • Weight > 21kg.

Exclusion Criteria:

  • Unable to read English;
  • Female patients who are pregnant or breastfeeding;
  • Life expectancy severely limited by diseases other than malignancy.

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 identifier (NCT number): NCT02291965

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United States, Washington
University of Washington
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
University of Washington
Seattle Children's Hospital
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Principal Investigator: Jeannine S. McCune, PharmD University of Washington
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Responsible Party: Fred Hutchinson Cancer Research Center Identifier: NCT02291965    
Other Study ID Numbers: 9117
First Posted: November 17, 2014    Key Record Dates
Last Update Posted: May 5, 2020
Last Verified: May 2020
Keywords provided by Fred Hutchinson Cancer Research Center:
hematopoietic cell transplant
Additional relevant MeSH terms:
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Multiple Myeloma
Myelodysplastic Syndromes
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases