Target Busulfan Exposure in Children With HSCT in China

Hematopoietic Stem Cell Transplantation Clinical Trial

Official title:

The Therapeutic Window of Busulfan in Children With Haemopoietic Stem Cell Transplantation：A Multicenter Study in China

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04786002
• Other study ID #: 2019-KY-BXA-01
• Status: Recruiting
• Start date: November 1, 2020
• Est. completion date: June 1, 2023

Study information

• Verified date: March 2021
• Source: The First Affiliated Hospital of Soochow University
• Contact: Chenrong Huang, PhD
• Phone: 86-512-67972699
• Email: chrishuangcr[@]163.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Objectives To evaluate the correlation between BU exposure and post-transplant clinical results (efficacy and safety) to establish the optimal BU treatment window for myeloablative conditioning in Chinese pediatrics, provide theoretical basis and the new strategy for BU individualized dosage, further optimize transplant treatment and reduce drug-related toxicity.

Population 500 participants of any sex between the age of 0.1 and 18 years. Patients receiving the BU-based myeloablative conditioning before transplantation.

Endpoint primary To establish BU pop-PK model and analyze the association between BU AUC and event-free survival (EFS)or overall survival (OS) after transplantation in Chinese pediatrics.

Secondary The investigators are also interested in transplantation-related mortality (TRM), acute toxicity and chronic GvHD.

Description:

Objectives To evaluate the influence factors of BU metabolism in children and the correlation between BU exposure and post-transplant clinical results (efficacy and safety) to establish the optimal BU treatment window for myeloablative conditioning in Chinese pediatrics, provide theoretical basis and the new strategy for BU individualized dosage, further optimize transplant treatment and reduce drug-related toxicity.

Endpoint primary The main study endpoints are event-free survival (EFS) and overall survival (OS). EFS is calculated from the time of transplant until death, relapse of disease, or graft failure (defined as non-engraftment or rejection), whichever occurred first. OS is the time between transplantation and death of any cause. All surviving patients are censored at day of last contact. Duration of follow-up is the time from transplant to the last assessment for surviving patients or death.

Secondary The investigators are also interested in transplantation-related mortality (TRM), acute toxicity and chronic GvHD. TRM is defined as death unrelated to underlying disease. Acute toxicities are defined as VOD (diagnosed according to modified Seattle criteria), acute GvHD grade II-IV (diagnosed and graded according to Mount Sinai Acute GvHD International Consortium (MAGIC) criteria, oral mucositis (grade II-IV) and hemorrhagic cystitis (grade II-IV). Two of the most commonly utilised scales for oral mucositis are the WHO and NCI-CTCAE scales. Chronic GvHD should be graded as mild, moderate or severe according to the National Institutes of Health (NIH) consensus criteria.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: June 1, 2023
• Est. primary completion date: December 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

1. The subjects or their legal guardians voluntarily sign the informed consent, and can complete the study in accordance with the requirements of the program;

2. No age or gender restriction;

3. Patients with blood disease confirmed by histopathology or cytology;

4. BU-based regimen will be adopted. The BU administration regimen was four times a day (Q6h), continuous intravenous infusion for 2 hours, 3 or 4 days in a row.

Exclusion Criteria:

1. Patients with difficulty in vein blood sampling (if there is a needle, blood history);

2. BU TDM was not performed during the treatment;

3. Subjects who are considered unfit to participate in the trail by the investigator.

Related Conditions & MeSH terms

• Hematopoietic Stem Cell Transplantation

Intervention

Drug:
• Busulfan
The BU administration regimen was four times a day (Q6h), continuous intravenous infusion for 2 hours, 3 or 4 days in a row.

Locations

Country	Name	City	State
China	the First Affiliated Hospital of Soochow University	Suzhou	Jiangsu

Sponsors (9)

Lead Sponsor	Collaborator
The First Affiliated Hospital of Soochow University	Beijing Children's Hospital, Children's Hospital of Fudan University, Children's Hospital Of Soochow University, Fujian Medical University Union Hospital, Guangzhou Women and Children's Medical Center, Shenzhen Children's Hospital, The First Affiliated Hospital of Zhengzhou University, West China Second University Hospital

Country where clinical trial is conducted

China, 

References & Publications (6)

Ansari M, Théoret Y, Rezgui MA, Peters C, Mezziani S, Desjean C, Vachon MF, Champagne MA, Duval M, Krajinovic M, Bittencourt H; Pediatric Disease Working Parties of the European Blood and Marrow Transplant Group. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. Ther Drug Monit. 2014 Feb;36(1):93-9. doi: 10.1097/FTD.0b013e3182a04fc7. — View Citation

Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, Egeler M, Lankester AC, Egberts AC, Zwaveling J, Boelens JJ. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):231-41. doi: 10.1016/j.bbmt.2008.11.022. — View Citation

Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, Bredius RG, Egberts AC, 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 GD, 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. Lancet Haematol. 2016 Nov;3(11):e526-e536. doi: 10.1016/S2352-3026(16)30114-4. Epub 2016 Oct 13. — View Citation

Dix SP, Wingard JR, Mullins RE, Jerkunica I, Davidson TG, Gilmore CE, York RC, Lin LS, Devine SM, Geller RB, Heffner LT, Hillyer CD, Holland HK, Winton EF, Saral R. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. 1996 Feb;17(2):225-30. — View Citation

Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Huezo-Diaz Curtis P, Duval M, Théoret Y, Daudt LE, Litalien C, Ansari M, Krajinovic M, Bittencourt H. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. Br J Clin Pharmacol. 2018 Jul;84(7):1494-1504. doi: 10.1111/bcp.13566. Epub 2018 Apr 27. — View Citation

Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M, Wingard JR, Paci A, Hassan M, Bredeson C, Pidala J, Shah N, Shaughnessy P, Majhail N, Schriber J, Savani BN, Carpenter PA. Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant. 2016 Nov;22(11):1915-1925. doi: 10.1016/j.bbmt.2016.07.013. Epub 2016 Jul 29. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	event-free survival (EFS)	EFS is calculated from the time of transplant until death, relapse of disease, or graft failure (defined as non-engraftment or rejection), whichever occurred first.	2 years after administration of busulfan
Primary	overall survival (OS)	OS is the time between transplantation and death of any cause.	2 years after administration of busulfan
Secondary	transplantation-related mortality (TRM)	TRM is defined as death unrelated to underlying disease.	2 years after administration of busulfan
Secondary	acute toxicity	Acute toxicities are defined as VOD (diagnosed according to modified Seattle criteria),, acute GvHD grade II-IV (diagnosed and graded according to Mount Sinai Acute GvHD International Consortium (MAGIC) criteria, oral mucositis (grade II-IV) and hemorrhagic cystitis (grade II-IV). Two of the most commonly utilised scales for oral mucositis are the WHO and NCI-CTCAE scales.	2 years after administration of busulfan
Secondary	chronic GvHD	Chronic GvHD should be graded as mild, moderate or severe according to the National Institutes of Health (NIH) consensus criteria	2 years after administration of busulfan