Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies

Denise M. Adams; Cameron C. Trenor; Adrienne M. Hammill; Alexander A. Vinks; Manish N. Patel; Gulraiz Chaudry; Mary Sue Wentzel; Paula S. Mobberley; Lisa M. Campbell; Christine Brookbank; Anita Gupta; Carol Chute; Jennifer Eile; Jesse McKenna; Arnold C. Merrow; Lin Fei; Lindsey Hornung; Michael Seid; A. Roshni Dasgupta; Belinda H. Dickie; Ravindhra G. Elluru; Anne W. Lucky; Brian Weiss; Richard G. Azizkhan

doi:10.1542/peds.2015-3257

Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies

Denise M. Adams^*, Cameron C. Trenor, Adrienne M. Hammill, Alexander A. Vinks, Manish N. Patel, Gulraiz Chaudry, Mary Sue Wentzel, Paula S. Mobberley, Lisa M. Campbell, Christine Brookbank, Anita Gupta, Carol Chute, Jennifer Eile, Jesse McKenna, Arnold C. Merrow, Lin Fei, Lindsey Hornung, Michael Seid, A. Roshni Dasgupta, Belinda H. DickieRavindhra G. Elluru, Anne W. Lucky, Brian Weiss, Richard G. Azizkhan

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

653 Scopus citations

Abstract

BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/ bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/ laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Original language	English (US)
Article number	e20153257
Journal	Pediatrics
Volume	137
Issue number	2
DOIs	https://doi.org/10.1542/peds.2015-3257
State	Published - Feb 2016

Funding

Supported by the Offi ce of Orphan Products (RO1FD003712-04) to Dr Adams at Cincinnati Children''s Hospital Medical Center. Pfi zer Inc provided sirolimus but had no role in designing or conducting the study or in analyzing or reporting the data. This research was conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102), and fi nancial contributions from Harvard University and its affi liated academic health care centers. Funded by the National Institutes of Health (NIH).

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1542/peds.2015-3257

Cite this

Adams, D. M., Trenor, C. C., Hammill, A. M., Vinks, A. A., Patel, M. N., Chaudry, G., Wentzel, M. S., Mobberley, P. S., Campbell, L. M., Brookbank, C., Gupta, A., Chute, C., Eile, J., McKenna, J., Merrow, A. C., Fei, L., Hornung, L., Seid, M., Dasgupta, A. R., ... Azizkhan, R. G. (2016). Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics, 137(2), Article e20153257. https://doi.org/10.1542/peds.2015-3257

@article{d75aa1b8b9a64c6e9f2115017a51a772,

title = "Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies",

abstract = "BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/ bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/ laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.",

author = "Adams, {Denise M.} and Trenor, {Cameron C.} and Hammill, {Adrienne M.} and Vinks, {Alexander A.} and Patel, {Manish N.} and Gulraiz Chaudry and Wentzel, {Mary Sue} and Mobberley, {Paula S.} and Campbell, {Lisa M.} and Christine Brookbank and Anita Gupta and Carol Chute and Jennifer Eile and Jesse McKenna and Merrow, {Arnold C.} and Lin Fei and Lindsey Hornung and Michael Seid and Dasgupta, {A. Roshni} and Dickie, {Belinda H.} and Elluru, {Ravindhra G.} and Lucky, {Anne W.} and Brian Weiss and Azizkhan, {Richard G.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2016 by the American Academy of Pediatrics.",

year = "2016",

month = feb,

doi = "10.1542/peds.2015-3257",

language = "English (US)",

volume = "137",

journal = "Pediatrics",

issn = "0031-4005",

publisher = "American Academy of Pediatrics",

number = "2",

}

Adams, DM, Trenor, CC, Hammill, AM, Vinks, AA, Patel, MN, Chaudry, G, Wentzel, MS, Mobberley, PS, Campbell, LM, Brookbank, C, Gupta, A, Chute, C, Eile, J, McKenna, J, Merrow, AC, Fei, L, Hornung, L, Seid, M, Dasgupta, AR, Dickie, BH, Elluru, RG, Lucky, AW, Weiss, B & Azizkhan, RG 2016, 'Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies', Pediatrics, vol. 137, no. 2, e20153257. https://doi.org/10.1542/peds.2015-3257

TY - JOUR

T1 - Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies

AU - Adams, Denise M.

AU - Trenor, Cameron C.

AU - Hammill, Adrienne M.

AU - Vinks, Alexander A.

AU - Patel, Manish N.

AU - Chaudry, Gulraiz

AU - Wentzel, Mary Sue

AU - Mobberley, Paula S.

AU - Campbell, Lisa M.

AU - Brookbank, Christine

AU - Gupta, Anita

AU - Chute, Carol

AU - Eile, Jennifer

AU - McKenna, Jesse

AU - Merrow, Arnold C.

AU - Fei, Lin

AU - Hornung, Lindsey

AU - Seid, Michael

AU - Dasgupta, A. Roshni

AU - Dickie, Belinda H.

AU - Elluru, Ravindhra G.

AU - Lucky, Anne W.

AU - Weiss, Brian

AU - Azizkhan, Richard G.

PY - 2016/2

Y1 - 2016/2

N2 - BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/ bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/ laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

AB - BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/ bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/ laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

UR - http://www.scopus.com/inward/record.url?scp=84958720517&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958720517&partnerID=8YFLogxK

U2 - 10.1542/peds.2015-3257

DO - 10.1542/peds.2015-3257

M3 - Article

C2 - 26783326

AN - SCOPUS:84958720517

SN - 0031-4005

VL - 137

JO - Pediatrics

JF - Pediatrics

IS - 2

M1 - e20153257

ER -

Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this