multicenter international lam efficacy of sirolimus (miles) trial

Multicenter International LAM Efficacy of Sirolimus (MILES) Trial

Francis X. McCormack, M.D., Yoshikazu Inoue, M.D., Ph.D., Joel Moss, M.D., Ph. D., Lianne G. Singer, M.D., Charlie Strange, M.D., Koh Nakata, M.D., Ph.D., Alan F. Barker, M.D., Jeffrey T. Chapman, M.D., Mark L. Brantly, M.D., James M. Stocks, M.D., Kevin K. Brown, M.D., Joseph P. Lynch, 3rd, M.D., Hilary J. Goldberg, M.D., Lisa R. Young, M.D., Brent W. Kinder, M.D., Gregory P. Downey, M.D., Eugene J. Sullivan, M.D., Thomas V. Colby, M.D., Roy T. McKay, Ph.D, Marsha M. Cohen, M.D., Leslie Korbee, B.S., Angelo M. Taveira-DaSilva, M.D., Ph.D., Hye-Seung Lee, Ph.D., Jeffrey P. Krischer, Ph. D, and Bruce C. Trapnell, M.D., for the NIH Rare Lung Diseases Consortium and the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) Trial

• Patent– “Use of VEGF-D as a diagnostic test in LAM”

• royalties directed to The LAM Foundation

• Pharmaceutical contributions to trials– CAST

• Wyeth = drug – MILES

• Wyeth (Pfizer) = drug + $200,000 for cost of trial conduct– TRAIL

• Novartis = drug + placebo– RAD001x2201

• Novartis = cost of trial conduct

Disclosure statement

Rationale

• TSC1 and TSC2 gene mutations cause LAM (Carsillo & Henske; PNAS, 2000)

• TSC proteins regulate signaling through the mTOR pathway (Ito & Rubin; Cell, 1999)

• The lung lesions in LAM exhibit mTOR activation (Goncharova & Krymskaya; JBC, 2002)

• Constitutive mTOR activation that occurs in LAM cells is inhibited by sirolimus (rapamycin) (Goncharova & Krymskaya; JBC, 2002)

• Sirolimus results in regression and apoptosis of renal tumors in TSC rodent models (Kennerson & Yeung; Cancer Re,s 2002).

In CAST patients with TSC or LAM, angiomyolipomas shrunk by 50% and lung function improved by 7-13%

NEJM 2008:358, 140-51 Lung Function by spirometry

Kidney tumor size by MRI

The MILES TrialMulticenter International LAM Efficacy of Sirolimus Trial

• Hypothesis– Treatment of LAM patients with sirolimus for one year

will lead to an improvement in FEV1.

NCT00414648

The MILES TrialMulticenter International LAM Efficacy of Sirolimus Trial

• Supported by the Office of Rare Disease Research Rare Lung Disease Consortium

• Regulatory oversight-National Center for Research Resources

• LAM Foundation assisted with recruitment and study logistics

• PI-Frank McCormack, M.D.• Primary site-Univ. of Cincinnati/Cincinnati Children’s• 12 other sites-9 domestic, 2 Japan, 1 Canada• Enrollment-Opened 12/06, Closed 8/09• Target-60 patients per armNCT00414648

7

The MILES TrialDesign:

A Phase III Treatment, Randomized (1:1), Double-Blind, Placebo Control, Intention to Treat, Safety/Efficacy Study

Subjects:Adult subjects (18+ years old) with LAM

Primary Aim:To determine the safety and efficacy of sirolimus in subjects with LAM

DurationTwo years-1 year treatment period, 1 year observation off

treatment

Primary Endpoint:Difference between the placebo and sirolimus groups in the rate of change (slope) in forced expiratory volume in 1 second

Statistics

• Conducted according to the “Intention to Treat” Principle

• Linear mixed effects model– Primary outcome method– Used to evaluate between group and within group

differences in FEV1 slope – Slope calculated from baseline, 3,6,9 and 12 month

data– Data from every patient that took drug included,

missing data not imputed

MILES Timeline

2005 2006 2007 2008 2009 2010 2011

FDAIND

Cincinnati open

MUSCopen

Other sitesOpen

DSMBRevisions

EnrollmentCloses

Last Visit

InterimAnalysis

2004

Protocol drafting

MILESFinal

AnalysisNCT00414648

MILESPublished

MILES eligibility

• Inclusion– Compatible CT +

• Biopsy or• Angiomyolipoma, tuberous sclerosis or chylothorax or• VEGFD ≥ 800 pg/ml (added in 2009)*

– Post bronchodilator FEV1 ≤ 70% predicted• Exclusion– Active on transplant list– Large pleural effusion– On other investigational agents

NCT00414648 *Young & McCormack Chest 2010

111 Patients consented

89 Patients randomized

43 Assigned to Placebo 46 Assigned to Sirolimus

22 ineligible• 18 FEV1 >70%

• 3 LAM diagnosis unclear• 1 Pleural effusion

MILES Trial SitesRare Lung Disease Consortium

OsakaNiigata

Toronto

Niigata

Data center

Osaka

2

7

1019

5

2

4

1

5

19

5

7

3

NCT00414648

MILES subjectsQualifying Inclusion Criteria

Inclusion CriteriaAll patients

(n = 89)Placebo Group

(n = 43)Sirolimus Group

(n = 46) P Value Biopsy, n (%) 54 (61%) 25 (58%) 29 (63%) 0.887¶

Clinical context, n (%) 23 (26%) 12 (28%) 11 (24%)

VEGF-D, n (%) 12 (13%) 6 (14%) 6 (13%)

MILES subjectsDemographics

CharacteristicAll patients



(n = 46) P ValueAge (years)

Mean ± S.D. 45.4 ± 10.6 45.9 ± 10.3 45.0 ± 10.9 0.736

Race

Caucasian, n (%) 59 (66) 30 (71) 29 (63) 0.581

Asian, n (%) 27 (30) 12 (28) 15 (33)

Other, n (%) 3 (3) 1 (2) 2 (4)

MILES subjectsClinical Features




(n = 46) P ValueHistorical Features Tuberous sclerosis complex, n (%) 8 (9) 4 (9) 4 (9) 1.000 Post-menopause, n (%) 30 (34) 16 (37) 14 (30) 0.499 History of angiomyolipoma, n (%) 44 (49) 22 (51) 22 (48) 0.753 History of pneumothorax, n (%) 53 (60) 29 (67) 24 (52) 0.143Oxygen therapy requirement Continuous use, n (%) 28 (32) 14 (33) 14 (30) 0.829

Intermittent use, n (%) 52 (58) 23 (54) 29 (63) 0.361

MILESBaseline Pulmonary Function

(% predicted)




(n = 46) P ValueFEV1 48.54 ± 13.77 47.73 ± 14.37 49.29 ± 13.31 0.771

FVC 79.71 ± 16.60 80.77 ± 17.62 78.73 ± 15.70 0.546

TLC 105.21 ± 25.63 106.70 ± 29.45 103.83 ± 21.71 0.607

FRC 112.49 ± 31.32 116.61 ± 38.29 108.67 ± 22.97 0.429

RV 141.42 ± 59.22 147.48 ± 69.25 135.78 ± 48.15 0.802

DLC0 43.43 ±18.97 43.77 ±20.56 43.12 ±17.66 0.699

MILES subjects had moderately severe obstructive lung disease with air trapping and a reduced diffusing capacity for carbon monoxide

3 mo 6 mo 9 mo 12 mo 18 mo 24 moBaseline

TREATMENT PERIOD-sirolimus vs. placebo OBSERVATION PERIOD-no treatment

3 wk

PFTs

ResearchSample

QOL

6MWD

visits

Visit calendar

Sirolimuslevel

HRCT

Randomize

Study article

• Patients were randomized to sirolimus 2 mg or an identical appearing placebo in a 1:1 ratio

• Sirolimus levels obtained at every visit after baseline and the dose was adjusted by medical monitor at the Data Center to maintain the serum level between 5-15 mg/ml

• Concomitant sham dose adjustments were made in the placebo group to maintain the blind

111 Patients consented

89 Patients randomized

43 Assigned to Placebo 46 Assigned to Sirolimus1 Withdrew2 PFT unable

3 Withdrew

3 Withdrew2 PFT unable

2 Withdrew1 PFT unable

3 Withdrew

3 PFT unable

40 with 3 mo data available








22 ineligible• 18 FEV1 >70%

• 3 LAM diagnosis unclear• 1 Pleural effusion

TREATMENT

OBSERVATION

Interim analysisFebruary 2010

• Stopping rule for efficacy was met (investigators later learned)

• DSMB recommended continuing trial until all treatment period data was collected

• DSMB endorsed an investigator-initiated plan to truncate the observation period, owing to termination of the funding period

• All MILES investigators and patients remained blinded to the treatment assignment until the final analysis was complete

2 Withdrew12 Early

termination

3 Withdrew6 Early

termination

6 Withdrew13 Early

termination1 PFT unable

1 Withdrew6 Early

termination1 PFT unable

OBSERVATION





MILES enrollment and attrition• Target 120• Total consented 111• Total enrolled 89

– Attrition• Treatment period

– Withdrawal 13– Death (house fire) 1

• Observation period– Withdrawal 12– Early termination 37– Death (stroke) 1

• Completed 12 months 75• Completed 24 months 27

NCT00414648

Individual FEV1 curves from 89 patients

The primary endpoint was met.FEV1 fell over the course of 1 yr on placebo and stabilized on sirolimus

*p<0.0001

FEV1 slope was -12±2 ml/mo. (placebo) vs. 1±2 ml/mo. (sirolimus)

FEV1 stabilized on sirolimus while treatment continued and declined in parallel with the placebo

group when drug was stopped

At the end of the treatment period, FEV1 stabilized or improved for 46% of patients on sirolimus vs.

12% on placebo

*p<0.001

Over the treatment period, the mean change in FEV1 was -134 ml in the placebo group and +19 ml on sirolimus; the between group difference

was 153 ml

153 ml

*p<0.001

Clinical relevance of an FEV1 difference of 153 ml?

• More than 10% of baseline FEV1 (1370 ml)• It compares favorably with the minimal clinically

important difference (MCID) in FEV1 of 100-140 ml estimate for COPD1 which:– can be perceived by patients– is typical for bronchodilator response– correlates with relapse after exacerbation

• Stabilization may delay transplantation and associated risks

1Donohoue JF COPD 2005

Secondary endpoints which were significantly different between the groups

• Forced vital capacity (FVC)• Functional residual capacity (FRC)• Quality of life visual analog scale (EuroQOL VAS)• Functional performance inventory (FPI)

MILESIndividual FVC curves for 89 subjects

MILESFVC slope increased on sirolimus

*P<0.0001FVC slope was -11±2 ml/mo. (placebo) vs. 8±3 ml/mo. (sirolimus)

MILESFVC fell in patients on placebo and improved on sirolimus

p<0.001

At the end of the treatment period, FVC was at or above baseline for 54% of patients on sirolimus, compared to 23 %

on placebo

<-15%

-15% to -10%

-10% to -5%

-5% to 0

0 to 5%

5% to 10%

10% to 15%

≥15%

25% 20% 15% 10% 5% 0% 5% 10% 15% 20% 25%

Placebo Sirolimus

Frequency (%)

FVC

%ch

ange

from

bas

elin

e to

1ye

ar

p<0.001

Over the treatment period, the mean change in FVC was -129 ml in the placebo group and +97 ml on

sirolimus; the between-group difference was 226 ml

226 ml

*

*p=0.001

How clinically important is a 226 ml change in FVC?

• 8% of the baseline FVC• Close to the estimated Minimum Clinically

Important Difference for Scleroderma of 250 ml

Khanna D. Clin Exper Rheumatol 2010

The increase in FVC on sirolimus was accompanied by an increase in the slope for FRC (and similar, though

not significant, trends in RV and TLC) suggesting relief from restriction as a mechanism of increased airflow

*p=0.049

RV FRC TLC*

placebosirolimus

Sirolimus resulted in an increase in the slope of the Functional Performance Inventory and Quality of Life visual analogue scale score

*p=0.03

*

Sirolimus resulted in an increase in the slope of the Functional Performance Inventory score

*

*p=0.03

Serum VEGF-D was stable in the placebo group and declined on sirolimus

*P<0.001 at 12 months

In fact, VEGF-D levels tended to increase when the drug was withdrawn

Secondary endpoints which were not different between the groups

• 6 minute walk test distance (6MWD)• Diffusing capacity for carbon monoxide (DLCO)• Total lung capacity (TLC)• Residual volume (RV)• St. George Respiratory Questionnaire (SGRQ)• SF-36 (SF-36)• General Well Being Questionnaire (GWB)

Associated with increased rate of lung function decline in the placebo group?

• Yes– Higher baseline FVC (above the median (2.79L))– Premenopausal status

• No– History of AML– Need for supplemental oxygen– History of pneumothorax– Baseline FEV1

Associated with treatment response?

• Yes– Higher baseline FVC (above the median (2.79L))– Premenopausal status– Higher baseline VEGF-D

• No– History of an AML– Need for supplemental oxygen– History of a pneumothorax– Baseline FEV1

Serum VEGF-D appears promising as a biomarker of disease severity, and perhaps

disease progression and treatment response, but MILES analysis confounded by:

• the use of VEGF-D as both an eligibility criterion and an outcome

• The high termination and withdrawal rate in the observation year

Adverse events

• Most common– Mouth ulcers– Diarrhea– Nausea– Elevated cholesterol– Acne-like rash– Lower extremity swelling

Adverse event categories

Adverse Events Serious Adverse EventsTreatment† Observation† Treatment† Observation†

Placebo Sirolimus Placebo Sirolimus Placebo Sirolimus Placebo Sirolimus

Blood/Bone Marrow 4 12 1 0 0 1 0 0

Cardiac Arrhythmia 0 2 0 2

Cardiac General 12 15 3 2 0 5 0 0

Constitutional Symptoms 35 46 7 7

Death not related to event 0 0 1 0 0 0 1 0

Dermatology/Skin 41 106 8 11

Gastrointestinal 181 275 12 20 1 3 0 0

Hemorrhage/Bleeding 14 17 3 1 0 0 1‡ 0

Infection 74 78 20 24 3 2 1 0

Lymphatic 8 15 6 0

Metabolic 26 56 1 6 0 1 0 0

Musculoskeletal 21 35 2 4 0 1 0 1

Ocular/Visual 3 8 1 2

Pain 115 130 9 13 1 7 0 0

Pulmonary/Upper Resp 121 97 17 32 13 2 0 0

Renal/Genitourinary 8 11 0 2

Total # adverse events 718 959 99 135 18 23 5 1

Treatment period Observation period

placebo sirolimus placebo sirolimus

Serious 8 0 0 0

Not serious 2 2 0 3

Total # ptx 10 2 0 3

MILESPneumothorax

Treatment period Observation period

placebo sirolimus placebo sirolimus

Definitely not related 1 11 2 1

Probably not related 8 7 0 0

Possibly related 5 3 3 0

Probably related 4 2 0 0

Total # serious adverse events

18 23 5 1

MILESRelatedness of serious adverse events

Conclusions

• Sirolimus stabilized FEV1 and improved FVC• Sirolimus improved quality of life and measures of

functional performance• Sirolimus did not improve measures of exercise

tolerance (6MWD) or gas exchange (DLCO)• Side effects were more common in the sirolimus

group but serious events were balanced between groups and the safety profile was acceptable

• Benefit persisted only while drug continued

Compared to subjects in the LAM Registry, lung function impairment was more severe in MILES

subjects

MILESn = 89

LAM Registryn = 230

FEV1 48.5 70.3

FVC 79.7 87.5

TLC 105.2 95.8

FRC 112.5 109.9

RV 141.4 125.4

DLC0 43.4 67.6

Ryu et al. AJRCCM 173:105, 2006

% predicted

Next questions to be answered with sirolimus/everolimus

• How much?– Could a lower dose produce similar benefit?

• How early?– Does sirolimus prevent progression if given early?

• How long?– Is benefit sustained beyond one year if drug continues?

• Who to treat?– Are there markers that predict who will progress and respond?

• How risky?– Short term and long term risk/benefit needs to be defined, especially

with longer courses of drug.

National Institutes of Health Rare Lung Diseases ConsortiumSponsor: Office of Rare Disease Research, Director: Steve Groft, PharmD

Administered by: National Center for Research Resources, Director: Barbara Alving MD, Elaine Collier MD, Carl Hunt MDData Management and Monitoring Center: University of South Florida, Director: Jeffrey Krischer, Ph.D.

Rare Lung Diseases Consortium LeadershipDirector: Bruce Trapnell, M.D.

Co-director: Frank McCormack, M.D.DSMB Chair: Robert Senior, M.D., Jay Ryu MD, Kevin Flaherty MD, JP Clancy MD

Translational Research Trials Office, Cincinnati Children's Hospital Medical CenterMedical Director: Timothy P. Cripe, M.D., Ph.D.

Clinical Research Manager: Sheri Uber

MILES LeadershipMILES Principal Investigator: Frank McCormack, M.D.

MILES Core Pathologist: Thomas Colby, M.D.MILES Core Radiologists: Cristopher Meyer, M.D. and Alan Brody, M.D.

MILES Pulmonary Function Core Director: Roy McKay, Ph.D.MILES Biomarker Core Director: Lisa Young, M.D.

MILES QOL Core Director: Marsha M. Cohen, M.D.MILES Statistician: Hye-Seung Lee, Ph.D.

MILES Project Manager: Leslie Korbee, B.S.MILES Lead Research Nurse: Susan McMahan, R.N.

Thanks

SITESBrigham and Women's Hospital-H. Goldberg (PI), F. Jacobson, E. Peters, I. RosasCleveland Clinic Foundation-J. Chapman (PI), D. Culver, D. Faile, M. MezianeMedical University of South Carolina-C. Strange (PI), A Gitter, J. Ravenel, S. SahnNational Heart, Lung, and Blood Institute- J. Moss (PI), A. Taveira-DaSilva, M. Vaughan, P. Barnes, S.

El-Chemaly, O. Hathaway, M. Haughey, C. Love, J. StarlingNational Jewish Medical and Research Center-K. Brown (PI), G. Cosgrove, G. Downey, S. Frankel, J.

Swigris, D. Kervitsky, M. Morrison, E. Perez, J. SchroederNational Hospital Organization Kinki-Chou Chest Medical Center-Y. Inoue (PI), M. Akira, M.

Kitaichi, T. Arai, C. Sugimoto, K. Hirohata, Y. Okumizu, Y. Inoue, K. Kumagai, A. Kikuyama, A. Ohya, K. Tachibana, K. Komatsu, Y. Sato, H. Moriguchi, S. Hayashi, M. Sakatani

Niigata University Medical & Dental Hospital-K. Nakata (PI), H. Nakayama, M. Sasagawa, A. Sato, T. Takada, R. Tazawa, M. Terada, C. Kaneko

Oregon Health and Science University-A. Barker (PI), J. Gold, K. Kennie, S. Nonas, S. Primack University of California Los Angeles- J. Lynch (PI), E. Callahan, M. Fishbein, S. Golleher, P.

Lopez, R. SaggarUniversity of Cincinnati/Cincinnati Children's Hospital Medical Center-F. McCormack (PI) & B.

Trapnell (PI), J. Bailey, W. Blower, A. Brody, J. Dahlquist, R. Dosani, M. Hodgson, P. Kaiser, B. Kinder, L. Korbee, M. Kuhlmann, D. Lagory, R. McKay, S. McMahan, C. Meyer, T. Roads, M. Stamper, E. Turner, S. Uber, L. Young, W. Zhang

University of Florida-M. Brantly (PI), L. Gilbert, P. Schreck, A. LeongUniversity of Texas Health Science Ctr- Tyler-J. Stocks(PI), T. Allen, L. Couch, J. Hoeft, J.

Padinjarayweetil, V. Taskar.University Health Network/University of Toronto-L. Singer (PI) & G. Downey (PI), M. Sichitu, J.

Thenganatt

Thanks

MILES Funding (~$7.25 million)

• NCRR/NIH RLDC $3,000,000• FDA $1,200,000• Wyeth/Pfizer (inc. drug) $1,200,000• The LAM Foundation $500,000• CIHR (Canada) $200,000• Japanese Ministry Health $200,000• Tuberous Sclerosis Assoc. $200,000• Cincinnati Children’s $100,000• Adler Foundation $50,000

∆FEV1 vs. ∆VEGF-D

Mean change

multicenter international lam efficacy of sirolimus (miles) trial

Documents

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lam durationtwo years

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