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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 5th 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 LAM/TSC Untreated Sirolimus Hydroxychloroquine Sirolimus + + Cell Proliferation TORC1 - + 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 >1/3 DLT’s 1/3 DLT’s 0/3 DLT’s Add 3 patients to dose level 1/6 DLT’s Escalate to dose level i+1 >1/6 DLT’s 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 Study visits Week 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 EKG X X Urine pregnancy X X X X X CBC diff X X X X X X X X X Sirolimus levels Chest CT X CXR X MRI abdomen X X X X X X X Full PFT X X X 6 MWT X X X X X Spirometry X X St George’s questionnaire X Ophthalmology exam 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 - 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 Elizabeth Henske Ivan Rosas Hilary Goldberg Danielle Morse Matt Hunninghake Phil Camp Betsy Peters Melissa Smith NIH Intramural Program Joel Moss Angelo Taveira-Dasilva Mary Haughey Funding: Department of Defense Contact info Souheil El-Chemaly, MD, MPH [email protected] Betsy Peters RN 617-525-9331 [email protected]