Transcript 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 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]