From bench to bedside: From bench to bedside: Current clinical trials in LAM Current clinical trials in LAM Souheil El-Chemaly, MD, MPH 2013 EPILEPSY CONFERENCE NYU Langone Medical Center May 5 th 2013 HARVARD MEDICAL SCHOOL BRIGHAM AND WOMEN’S HOSPITAL
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From bench to bedside: Current clinical trials in LAM
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 - PowerPoint PPT Presentation
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From bench to bedside: From bench to bedside: Current clinical trials in LAMCurrent clinical trials in LAM
Souheil El-Chemaly, MD, MPH
2013 EPILEPSY CONFERENCE
NYU Langone Medical Center
May 5th 2013
HARVARDMEDICAL SCHOOL
BRIGHAM ANDWOMEN’S HOSPITAL
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):3807–3816McCormack 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 bedside1- 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
TORC1
Cell Proliferation Autophagy
Sirolimus
+
+ -
-
-
-
-+-
UntreatedSirolimus
Hydroxychloroquine
LAM/TSC
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
1/3 DLT’s >1/3 DLT’s0/3 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
Enter 3 patients at dose level i
Dose escalation scheme
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
Study visitsWeek
Baseline 3 8 16 24 36 48
Visit number 1 2 3 4 5 6 7
Drug Administration Record X X X X X
Liver, renal, glucose, cholesterol X X X X X X
EKG X X X
Urine pregnancy X X X X X
CBC diff X X X X X
Sirolimus levels X X X X
Chest CT X
CXR X X X X
MRI abdomen X X X
Full PFT X X X
6 MWT X X X
Spirometry X
St George’s questionnaire X X X X
Ophthalmology exam X X
From bench to bedside2- Estrogen in LAM
Role of estrogen in LAM
Yu J et al. PNAS 2009 106 (8) 2635-2640 Li C et al. AJRCMB 2013 In Press
Faslodex (estrogen receptor antagonist)
TRAIL
• Trial of Aromatase Inhibition in LAM
• Phase 2 trial - Letrozole nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) 2.5mg po daily
OR
- 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)
SAIL Trial Team
BWH LAM team NIH Intramural Program
Elizabeth Henske Joel MossIvan Rosas Angelo Taveira-
DasilvaHilary Goldberg Mary HaugheyDanielle MorseMatt HunninghakePhil CampBetsy PetersMelissa Smith