BRIGHAM AND
WOMEN’S HOSPITAL
HARVARD
MEDICAL SCHOOL
From bench to bedside:
Current clinical trials in LAM
Souheil El-Chemaly, MD, MPH
2013 EPILEPSY CONFERENCE
NYU Langone Medical Center
May 5 th 2013

Disclosures
• No conflict of interest

TSC and LAM
• Incidence of LAM in TSC
- The risk of LAM was age-dependent, rising by about 8% per year.
- Prevalence of LAM was 27% in subjects <21 years and 81% in subjects >40 years.
• Clinically significant LAM in TSC
- 63% developed pulmonary symptoms
- 12.5% died due to LAM.
Young et al. Chest. In press

Rapalogues
Bissler et al. NEJM 2008; 358:140-151

The MILES trial
McCormack FX et al. NEJM 2011364(17):1595-606

How do we preserve lung function?

Different approaches
• Disease suppression
• Remission induction
Henske EP et al. J Clin Invest. 2012;122(11):3807
–3816
McCormack et al. AJRCCM 2012; 186 (12):1210-1212.

Disease suppression
Taveira-DaSilva et al. Ann Intern Med 2011 154 (12):797-805

From bench to bedside
1- Autophagy inhibition

Autophagy
• “Self-eating”
• Garbage disposal for cells, which use the breakdown products to fuel energy production and to replenish building blocks for proteins and other essential molecules
• Increased autophagy can lead to cell survival
• mTORC1 is a known inhibitor of autophagy

Inhibition of mTORC1 and autophagy
Parkhitko et al. PNAS (2011); 108:12455-60

Untreated
LAM/TSC
Sirolimus
Hydroxychloroquine
-
+
TORC1
-
Sirolimus
+
-
Cell Proliferation
-
+
-
Autophagy
-

SAIL trial

SAIL trial
• Sirolimus and Autophagy Inhibition in LAM
• Phase I dose escalation study
- Sirolimus (same doses used in MILES).
- Hydroxychloroquine (dose escalation)
Clinicaltrials.gov NCT01687179
Sponsored by the Department of Defense

Dose escalation scheme
Enter 3 patients at dose level i
0/3 DLT’s 1/3 DLT’s >1/3 DLT’s
Add 3 patients to dose level
1/6 DLT’s >1/6 DLT’s
Escalate to dose level i+1 Stop and declare dose level i-1 as the MTD

Objectives
• Primary endpoint
-Safety and tolerability of HCQ+Sirolimus
• Secondary endpoint
- To evaluate lung function,6MWT, AML size, and quality of life.
• Exploratory endpoint
- Metabolomics, cytokines and circulating LAM cells

Inclusion criteria
• Female age 18 or older
• Diagnosis of LAM
– CT chest compatible with LAM and a biopsy or cytology consistent with
LAM.
– CT chest consistent with LAM in the setting of tuberous sclerosis, renal
AML, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen or serum VEGF-D > 800 pg/uL.
• Post bronchodilator FEV1 ≤80% predicted or DLCO
≤70% predicted or RV≥120% predicted

Exclusion criteria
• Use of an investigational drug within 30 days
• Recent pneumothorax within 8 weeks
• History of malignancy in the last 2 years other than basal cell skin cancer
• Currently taking doxycycline, metformin, lupron or simvastatin
• Use of estrogen containing medication within 30 days

Visit number
Drug Administration Record
Liver, renal, glucose, cholesterol
EKG
Urine pregnancy
CBC diff
Sirolimus levels
Chest CT
CXR
MRI abdomen
Full PFT
6 MWT
Spirometry
St George
’ s questionnaire
Ophthalmology exam
Study visits
Week
Baseline
X
X
1
X
X
X
3
X
X
X
X
X
2
X
X
X
X
8
3
X
X
X
X
X
16
4
X
X
X
X
X
X
X
X
X
X
X
X
24
X
X
X
X
X
5
X
X
X
X
X
X
X
36
6
48
7
X
X
X
X
X
X

From bench to bedside
2- Estrogen in LAM

Role of estrogen in LAM
Faslodex (estrogen receptor antagonist)
Yu J et al. PNAS 2009 106 (8) 2635-2640 Li C et al. AJRCMB 2013 In Press

TRAIL
• Trial of Aromatase Inhibition in LAM
• Phase 2 trial
OR
- Letrozole nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) 2.5mg po daily
- Placebo
Clinicaltrials.gov NCT01353209

Inclusion criteria
• Post menopausal female
• Diagnosis of LAM
– CT chest compatible with LAM and a biopsy or cytology consistent with
LAM.
– CT chest consistent with LAM in the setting of tuberous sclerosis, renal
AML, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen or serum VEGF-D > 800 pg/uL.
• Post bronchodilator FEV1 ≤80% predicted or DLCO
≤70% predicted or RV≥120% predicted

Exclusion criteria
• Known allergy to letrozole
• Inability to comply with pulmonary function tests or follow up visits.
• Treatment with investigational agents within 30 days
• Hormonal therapy (e.g. estrogen, progestin, LHRH agonists or antagonists, estrogen receptor blockers, estrogen receptor down regulators, aromatase inhibitors) within 30 days month of registration
• Medical or psychiatric conditions that would interfere with the ability to provide informed consent.

Objectives
- Primary Outcome Measures:
- Effect on FEV1 at 12 months
- Secondary Outcome Measures:
- Effects on FVC, DLCO, TLC,RV, FRC, 6MWT at 12 months
- Effects on quality of life measures (QoL, dyspnea, fatigue, functional performance
- Serum VEGF-D level

Future direction in therapy
Henske EP et al. J Clin Invest. 2012;122(11):3807
–3816.

Summary
• Molecular insights have lead to targeted therapies in
LAM.
• Rapalogues alone are not sufficient. Additional drugs are needed
• Currently 2 clinical trials are recruiting in the US:
– SAIL (Sirolimus and Hydroxychloroquine)
– TRAIL (aromatase inhibitor)

BWH LAM team
Elizabeth Henske
Ivan Rosas
Hilary Goldberg
Danielle Morse
Matt Hunninghake
Phil Camp
Betsy Peters
Melissa Smith
SAIL Trial Team
NIH Intramural Program
Joel Moss
Angelo Taveira-Dasilva
Mary Haughey
Funding: Department of Defense

Contact info
Souheil El-Chemaly, MD, MPH sel-chemaly@partners.org
Betsy Peters RN
617-525-9331 epeters2@partners.org