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Trial registered on ANZCTR


Registration number
ACTRN12612000544875
Ethics application status
Approved
Date submitted
16/05/2012
Date registered
22/05/2012
Date last updated
2/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Pharmacokinetics, pharmacodynamics and pharmacogenomics of busulphan and other agents used in blood or marrow transplantation
Scientific title
Pharmacokinetics, pharmacodynamics and pharmacogenomics of busulphan and other agents used in blood or marrow transplantation
Secondary ID [1] 280486 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
acute leukaemia 286466 0
non-Hodgkin Lymphoma 286467 0
Multiple myeloma 286468 0
Pharmacokinetics of various chemotherapeutic agents used as conditioning in allogeneic and autologous transplant recipients 286530 0
Condition category
Condition code
Cancer 286724 286724 0 0
Leukaemia - Acute leukaemia
Cancer 286725 286725 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 286726 286726 0 0
Myeloma

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
By examining the pharmacokinetics (PK, dose versus concentration relationship), pharmacodynamics (PD, concentration versus effect relationship) and pharmacogenomics (genetic influences on PK and PD) of drugs used in blood or marrow transplantation, it may be possible to individualise the dose to enhance therapeutic efficacy, reduce toxicity and maximise the chance of disease control.

The aims of this project are to:

1. Examine the pharmacokinetics of busulphan and other drugs used in BMT conditioning and to identify sources of variability in the pharmacokinetic parameters
2. To examine whether there is an association between exposure to busulphan and other drugs and toxicity and/or outcome following BMT (pharmacodynamics)
3. To examine the influence of genetic factors on the pharmacokinetics of busulphan and other drugs and outcome following BMT. Outcome endpoints include frequency of servious (Grade 3 +) toxicity, as well as survival endpoints.
4. To investigate whether patients who get veno-occlusive disease of the liver (VOD) following busulphan-based conditioning use different metabolic pathways than those who do not.

The target population are patients scheduled to receive busulphan or other agents prior to autologous or allogeneic bone marrow transplantation.

The required blood and urine sampling will depend on the level of participation of the institution. Each institution can participate in any or all of four levels and this will be
determined by the Principal Investigator, who will make this decision at their own discretion based on factors including (1) the characteristics of the local patient population and the common toxicities seen at the site and (2) the availability of resources for trial participation Additionally, participants are also able to accept or decline certain levels of participation. on the consent form. Level 1 involves the collection of clinical data in patients having busulphan concentrations measured for routine pharmacokinetic assessment. Level 2 involves the collection of additional bloods to analyse the pharmacokinetics of BMT drugs other than busulphan. The actual drugs being studied will depend on the protocols being used. Random urine samples will also be collected before and on the last day of busulphan dosing to investigate differences in busulphan metabolism. Level 3 involves the collection of a single EDTA blood sample prior to BMT conditioning for pharmacogenomics tests. Level 4 involves the weekly collection of blood for metabolomics studies to investigate the pathogenesis of VOD. These bloods can be retrieved from Pathology following routine Biochemical tests.

Drug concentrations will be measured using the chromatographic equipment in the Department of Biochemistry at The Children’s Hospital at Westmead. Pharmacokinetic software (including Kinetica4.0 and NONMEM7.3) will be used to calculate the pharmacokinetic parameters for each patient, and to identify sources of pharmacokinetic variability (e.g .body size, patient age, diagnosis, concomitant medication, prior medication, renal function and pharmacogenomics traits). Statistical tests including logistic regression and multivariate cox proportional hazards regression will be used to identify whether drug exposure and other factors are significant contributors to toxicity and outcome after BMT. Patient outcome will be followed up to 5 years post transplant.

This information is important for developing optimal dosing strategies for BMT drugs and has the potential to reduce toxicity and improve outcomes following BMT.
Intervention code [1] 284854 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287123 0
To use drug concentrations measured in a series of timed blood collections to calculate the pharmacokinetic parameters of drugs used in the blood or marrow transplantation conditioning regimens and to identify how and why patients differ. Clinical data, including renal function, concomitant medication, genotype, weight and age, will be collected from medical records and tested for significant effects on pharmacokinetic parameters, thereby allowing identification of the factors which can contribute to inter and intra-patient variability.
Timepoint [1] 287123 0
Blood sampling and clinical data will be collected during the period of blood or marrow transplantation conditioning.
Primary outcome [2] 287126 0
To examine the association between exposure to drugs used in blood or marrow transplantation conditioning regimens and transplant outcome, including transplant -related toxicity, engraftment, survival, disease relapse and Graft versus Host Disease. Follow-up will continue for up to five years post transplant. outcome data will be collected from medical records.
Timepoint [2] 287126 0
Patients will be followed for up to five years from the date of blood or marrow transplantation conditioning.
Secondary outcome [1] 297444 0
To assess whether pharmacogenomic factors influence the pharmacokinetics, toxicity and outcome of patients undergoing blood or marrow transplantation
Timepoint [1] 297444 0
A single blood sample will be collected prior to starting conditioning
Secondary outcome [2] 334353 0
To investigate whether patients who get veno-occlusive disease of the liver (VOD) following busulphan-based conditioning use different metabolic pathways than those who do not. During the time of BMT conditioning and up to three months post BMT, the symptoms and signs of VOD will be recorded, including changes in albumin and bilirubin concentrations, increased platelet requirement, weight gain, hepatic tenderness and ascites. This data will be obtained from patient's medical records. Additionally, plasma samples will be collected before transplant and regularly post-transplant to monitor the changes occurring with development of VOD. In the pre-transplant period a targeted approach will be used to identify and quantify metabolites of drugs used during BMT conditioning (e.g. busulphan, melphalan and fludarabine). Chromatographic techniques will be used to separate and detect known drug metabolites and these will be quantified with reference stable isotopes using standard mass spectrometry methods. In the post transplant period, an untargeted approach will be used to characterise changes that occur with VOD. Bioinformatic analysis will be used to compare the drug metabolites and other analytes in patients who developed VOD versus those who did not.

Timepoint [2] 334353 0
Bloods will be collected every week from prior to BMT conditioning to up to three months post BMT, to investigate the pathogenesis of VOD.

Eligibility
Key inclusion criteria
1. Patients of any age receiving IV busulphan and /or other conditioning agents prior to autologous or allogeneic transplantation to treat both malignant and non-malignant disease.
2. Patients require adequate venous access preferably with a central venous catheter but will be as per institution’s transplant policy
3.Written informed consent
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Those for whom written informed consent cannot be obtained.

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 7909 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 7910 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 7911 0
Westmead Hospital - Westmead
Recruitment hospital [4] 7912 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [5] 7913 0
Liverpool Hospital - Liverpool
Recruitment hospital [6] 7914 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment postcode(s) [1] 15871 0
2145 - Westmead
Recruitment postcode(s) [2] 15872 0
2050 - Camperdown
Recruitment postcode(s) [3] 15873 0
2170 - Liverpool
Recruitment postcode(s) [4] 15874 0
2031 - Randwick
Recruitment postcode(s) [5] 15875 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 285252 0
Hospital
Name [1] 285252 0
The Children's Hospital at Westmead
Address [1] 285252 0
Hawkesbury Rd.
Westmead, NSW, 2145
Country [1] 285252 0
Australia
Primary sponsor type
Hospital
Name
The Children's Hospital at Westmead
Address
Hawkesbury Rd.
Westmead, NSW,2145.
Country
Australia
Secondary sponsor category [1] 284114 0
None
Name [1] 284114 0
Address [1] 284114 0
Country [1] 284114 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287258 0
Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 287258 0
The Children's Hospital at Westmead,
Hawkesbury Rd.
Westmead, NSW, 2145
Ethics committee country [1] 287258 0
Australia
Date submitted for ethics approval [1] 287258 0
07/09/2015
Approval date [1] 287258 0
16/11/2015
Ethics approval number [1] 287258 0
HREC/15/SCHN/355
Ethics committee name [2] 287271 0
Peter MacCallum Cancer Care Centre Ethics Committee
Ethics committee address [2] 287271 0
Level 4, #10 St Andrews Place,
East Melbourne,
Victoria, 3002
Ethics committee country [2] 287271 0
Australia
Date submitted for ethics approval [2] 287271 0
18/07/2011
Approval date [2] 287271 0
Ethics approval number [2] 287271 0
11/59

Summary
Brief summary
The primary purpose of this trial is to evaluate the relationship between drugs which are administered for blood or bone marrow transplants and the outcomes of the transplant. Who is it for? You may be eligible to enroll in this study if you are receiving intravenous busulphan and/or other conditioning agents prior to a blood or bone marrow transplant. Study details All participants enrolled in this study will have blood samples taken at different timepoints depending on the institution at which they are receiving treatment, but may be as frequent as weekly until three months following the transplant. Some of the samples will have been taken for clinical reasons and some additional samples are for research. Participants can choose how many additional samples they will contribute to the study. Researchers will review medical records to evaluate the clinical outcomes of the transplant, and participants will be followed-up for 5 years. It is hoped that by evaluating the concentration of these drugs in the body, and their longterm effects, it may be possible to individualise the dose given to patients to enhance efficacy, reduce toxicity and maximise the chance of disease control.
Trial website
Trial related presentations / publications
Publications
1. Bartelink I, Boelens J, Bredius R, Egberts A, Wang C, Bierings M, Shaw P, Nath C, Hempel G, Zwaveling J, Danhof M, Knibbe C. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation : towards individualised dosing. Clin. Pharmacokinet. 2012 ; 51 (5) : 331-345.
2. Bartelink I, Lalmohamed A, van Reij EML, Dvorak CC, Savic RM, Zwaveling J, Bredius RGM, Egberts ACG, Bierings M, Kletzel M, Shaw PJ, Nath CE, Hempel G, Ansari M, Krajinovic M, Théorêt Y, Duval M, Keizer RJ, Bittencourt H, Hassan M, Güngör T, Wynn RF, Veys P, Cuvelier GDE, Marktel S, Chiesa R, Cowan MJ, Slatter MA, Stricherz MK, Jennissen C, Long-Boyle JR, Boelens JJ. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. The Lancet Haematology, Vol. 3, No. 11, e526–e536 Published: October 13, 2016 DOI: http://dx.doi.org/10.1016/S2352-3026(16)30114-4
3. Cendana M, Lee S, Upadhyay PJ, Byrne JA, Shaw PJ, Earl JW, Nath CE. An HPLC-UV method for determining plasma dimethylacetamide concentrations in patients receiving intravenous busulphan. Biomedical Chromatography. Epub 21 Dec 2016 DOI: 10.1002/bmc.3906

Conference presentations
1. Bateman CM, Nath CE, Gabriel M, Keogh S, Lee S, Shaw PJ. Suboptimal Engraftment is Associated with reduced exposure to Fludarabine Metabolite in Children undergoing Allogeneic Haematopoietic Stem Cell Transplantation, Blood 2016; 128: 2189
2. Willcox A, Wong E, Janson B, Bajel A, Harrison S, Hoyt R, Nath CE, Shaw PJ, Ritchie D, Grigg A. A Multicentre Study Investigating The Pharmacokinetics And Pharmacodynamics Of Busulphan When Combined With Melphalan As Conditioning In Adult Autologous Transplant Recipients. Blood 2016 128:2190.
3. Bartelink IH et al. Busulfan Exposure Predicts Event Free Survival and Toxicity after Hematopoietic Cell Transplantation in Childrennd Young Adults: a Multicenter Retrospective Cohort Analysis Bone Marrow Transplantation 2016 Mar 1 (Vol. 51, pp. S14-S14).
4. Lalmohamed A. et al. Studying the Optimal Intravenous Busulfan Exposure in Pediatric Allogeneic Hematopoietic Cell Transplantation (alloHCT) to Improve Clinical Outcomes: A Multicenter Study. .Biology of Blood and Marrow Transplant 2015: Volume 21, Issue 2 , S102 - S103.
5. Shaw PJ, Ritchie DS, Gibson J, Larsen SR, Grigg A, Hertzberg M, Fay K and Nath CE. Not getting high on busulfan: A novel approach to avoid high busulfan levels in adults and children undergoing HSCT. ASBMT conference 2011. Biol. Blood Marrow Transplant. 2011 17:2 (Supplement), S315-S316.
6.. Bartelink IH, Boelens JJ, Bredius RGM, Egberts ACG, Biering M, Shaw P, Nath CE, Zwaveling J, Danhof M and Knibbe CAJ. Optimizing the busulfan dosing regimen to get a more predictable exposure: a data driven analysis. ASBMT conference 2011. Biol. Blood Marrow Transplant. 2011 17:2 (Supplement), S180.
7.. Shaw PJ, Ritchie DS, Gibson J, Larsen S, Grigg A, Hertzberg M, Fay K and Nath CE. Pharmacokinetic monitoring of single daily intravenous busulphan in adult patients undergoing Haemopoietic Progenitor Cell Transplantation. HAA Conference (Combined meeting of HSANZ, ANZSBT and ASTH), October 2010, Auckland New Zealand.
8. Bryant C, Larsen S, Iland H, Shaw PJ, Nath CE, Johnston AM, Cunningham I, Joshua DE and Gibson J. Safety and toxicity in patients undergoing allogeneic stem cell transplantation conditioned with fludarabine plus single daily intravenous busulphan with pharmacokinetic monitoring. HAA Conference (Combined meeting of HSANZ, ANZSBT and ASTH), October 2010, Auckland New Zealand.
Public notes

Contacts
Principal investigator
Name 34177 0
Prof Peter Shaw
Address 34177 0
Head, BMT Services,
The Children's Hospital at Westmead.
Hawkesbury Rd
Westmead, NSW, 2145
Country 34177 0
Australia
Phone 34177 0
61-2-98450000
Fax 34177 0
61-2- 98452171
Email 34177 0
peter.shaw@health.nsw.gov.au
Contact person for public queries
Name 17424 0
Dr Christa Nath
Address 17424 0
Department of Biochemistry,
The Children's Hospital at Westmead,
Hawkesbury Rd, Westmead NSW, 2145
Country 17424 0
Australia
Phone 17424 0
61-2-98453287
Fax 17424 0
61-2-98453332
Email 17424 0
christa.nath@health.nsw.gov.au
Contact person for scientific queries
Name 8352 0
Dr Christa Nath
Address 8352 0
Department of Biochemistry,
The Children's Hospital at Westmead,
Hawkesbury Rd, Westmead NSW, 2145
Country 8352 0
Australia
Phone 8352 0
61-2-98453287
Fax 8352 0
61-2-98453332
Email 8352 0
christa.nath@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
No Results