A Phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis

Calvin Lu, Hye Seung Lee, George P. Pappas, Daniel F. Dilling, Charles Dwayne Burger, Adrian Shifren, Srihari Veeraraghavan, Jeffrey T. Chapman, Joseph Parambil, Stephen J. Ruoss, Lisa R. Young, Stephen R. Hammes, Elizabeth J. Kopras, Tammy Roads, Jeffrey P. Krischer, Francis X. McCormack

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Rationale: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods: Seventeen postmenopausal women with LAM were enrolled in thisphase II trial andrandomized toreceive letrozole 2.5mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was 2363 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was 20.02460.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (20.02960.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, comparedwith only half of the patientswhowere not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the samemonth as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline.

Original languageEnglish (US)
Pages (from-to)919-928
Number of pages10
JournalAnnals of the American Thoracic Society
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2017

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letrozole
Lymphangioleiomyomatosis
Phase II Clinical Trials
Aromatase Inhibitors
Sirolimus
Vascular Endothelial Growth Factor D
Placebos
Estrogens
Therapeutics
Lung

Keywords

  • Aromatase
  • Estrogen suppression
  • Lymphangiomyomatosis
  • Steroid sensitive neoplasm
  • Vascular endothelial growth factor-D

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine

Cite this

A Phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis. / Lu, Calvin; Lee, Hye Seung; Pappas, George P.; Dilling, Daniel F.; Burger, Charles Dwayne; Shifren, Adrian; Veeraraghavan, Srihari; Chapman, Jeffrey T.; Parambil, Joseph; Ruoss, Stephen J.; Young, Lisa R.; Hammes, Stephen R.; Kopras, Elizabeth J.; Roads, Tammy; Krischer, Jeffrey P.; McCormack, Francis X.

In: Annals of the American Thoracic Society, Vol. 14, No. 6, 01.06.2017, p. 919-928.

Research output: Contribution to journalArticle

Lu, C, Lee, HS, Pappas, GP, Dilling, DF, Burger, CD, Shifren, A, Veeraraghavan, S, Chapman, JT, Parambil, J, Ruoss, SJ, Young, LR, Hammes, SR, Kopras, EJ, Roads, T, Krischer, JP & McCormack, FX 2017, 'A Phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis', Annals of the American Thoracic Society, vol. 14, no. 6, pp. 919-928. https://doi.org/10.1513/AnnalsATS.201610-824OC
Lu, Calvin ; Lee, Hye Seung ; Pappas, George P. ; Dilling, Daniel F. ; Burger, Charles Dwayne ; Shifren, Adrian ; Veeraraghavan, Srihari ; Chapman, Jeffrey T. ; Parambil, Joseph ; Ruoss, Stephen J. ; Young, Lisa R. ; Hammes, Stephen R. ; Kopras, Elizabeth J. ; Roads, Tammy ; Krischer, Jeffrey P. ; McCormack, Francis X. / A Phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis. In: Annals of the American Thoracic Society. 2017 ; Vol. 14, No. 6. pp. 919-928.
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abstract = "Rationale: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods: Seventeen postmenopausal women with LAM were enrolled in thisphase II trial andrandomized toreceive letrozole 2.5mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was 2363 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was 20.02460.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (20.02960.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, comparedwith only half of the patientswhowere not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the samemonth as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline.",
keywords = "Aromatase, Estrogen suppression, Lymphangiomyomatosis, Steroid sensitive neoplasm, Vascular endothelial growth factor-D",
author = "Calvin Lu and Lee, {Hye Seung} and Pappas, {George P.} and Dilling, {Daniel F.} and Burger, {Charles Dwayne} and Adrian Shifren and Srihari Veeraraghavan and Chapman, {Jeffrey T.} and Joseph Parambil and Ruoss, {Stephen J.} and Young, {Lisa R.} and Hammes, {Stephen R.} and Kopras, {Elizabeth J.} and Tammy Roads and Krischer, {Jeffrey P.} and McCormack, {Francis X.}",
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T1 - A Phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis

AU - Lu, Calvin

AU - Lee, Hye Seung

AU - Pappas, George P.

AU - Dilling, Daniel F.

AU - Burger, Charles Dwayne

AU - Shifren, Adrian

AU - Veeraraghavan, Srihari

AU - Chapman, Jeffrey T.

AU - Parambil, Joseph

AU - Ruoss, Stephen J.

AU - Young, Lisa R.

AU - Hammes, Stephen R.

AU - Kopras, Elizabeth J.

AU - Roads, Tammy

AU - Krischer, Jeffrey P.

AU - McCormack, Francis X.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Rationale: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods: Seventeen postmenopausal women with LAM were enrolled in thisphase II trial andrandomized toreceive letrozole 2.5mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was 2363 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was 20.02460.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (20.02960.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, comparedwith only half of the patientswhowere not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the samemonth as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline.

AB - Rationale: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods: Seventeen postmenopausal women with LAM were enrolled in thisphase II trial andrandomized toreceive letrozole 2.5mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was 2363 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was 20.02460.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (20.02960.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, comparedwith only half of the patientswhowere not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the samemonth as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline.

KW - Aromatase

KW - Estrogen suppression

KW - Lymphangiomyomatosis

KW - Steroid sensitive neoplasm

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