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

Funding: Department of Defense

Contact info

Souheil El-Chemaly, MD, MPH

sel-chemaly@partners.org

Betsy Peters RN

617-525-9331

epeters2@partners.org