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Multicenter International LAM Efficacy of Sirolimus (MILES) Trial

Multicenter International LAM Efficacy of Sirolimus (MILES) Trial.

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Multicenter International LAM Efficacy of Sirolimus (MILES) Trial

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  1. 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

  2. Disclosure statement • 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

  3. 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).

  4. In CAST patients with TSC or LAM, angiomyolipomas shrunk by 50% and lung function improved by 7-13% Kidney tumor size by MRI Lung Function by spirometry NEJM 2008:358, 140-51

  5. 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

  6. 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 arm NCT00414648

  7. The MILES Trial Design: 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 Duration Two 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 7

  8. 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

  9. MILES Timeline 2005 2006 2007 2008 2009 2010 2011 2004 Cincinnati open MUSC open Other sites Open Enrollment Closes DSMB Revisions Last Visit FDA IND Interim Analysis Protocol drafting MILES Published MILES Final Analysis NCT00414648

  10. 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

  11. 22 ineligible • 18 FEV1 >70% • 3 LAM diagnosis unclear • 1 Pleural effusion 111 Patients consented 89 Patients randomized 43 Assigned to Placebo 46 Assigned to Sirolimus

  12. MILES Trial SitesRare Lung Disease Consortium 5 Toronto 2 7 19 Osaka 5 10 19 2 1 7 5 3 Osaka Niigata Niigata 4 Data center NCT00414648

  13. MILES subjectsQualifying Inclusion Criteria

  14. MILES subjectsDemographics

  15. MILES subjectsClinical Features

  16. MILESBaseline Pulmonary Function (% predicted) MILES subjects had moderately severe obstructive lung disease with air trapping and a reduced diffusing capacity for carbon monoxide

  17. Visit calendar visits TREATMENT PERIOD-sirolimus vs. placebo OBSERVATION PERIOD-no treatment Randomize PFTs 3 mo 6 mo 9 mo 12 mo 18 mo 24 mo 3 wk Baseline QOL 6MWD Sirolimus level HRCT Research Sample

  18. 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

  19. 22 ineligible • 18 FEV1 >70% • 3 LAM diagnosis unclear • 1 Pleural effusion 111 Patients consented 89 Patients randomized 43 Assigned to Placebo 46 Assigned to Sirolimus 1 Withdrew 2 PFT unable 2 Withdrew 1 PFT unable T R E A T M E N T 40 with 3 mo data available 43 with 3 mo data available 3 Withdrew 42 with 6 mo data available 41 with 6 mo data available 3 Withdrew 3 PFT unable 38 with 9 mo data available 39 with 9 mo data available 3 Withdrew 2 PFT unable 41 with 12 mo data available 34 with 12 mo data available O B S E R V A T I O N

  20. 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

  21. O B S E R V A T I O N 6 Withdrew 13 Early termination 1 PFT unable 2 Withdrew 12 Early termination 21 with 18 mo data available 22 with 18 mo data available 1 Withdrew 6 Early termination 1 PFT unable 3 Withdrew 6 Early termination 14 with 24 mo data available 13 with 24 mo data available

  22. 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

  23. Individual FEV1 curves from 89 patients

  24. The primary endpoint was met.FEV1 fell over the course of 1 yr on placebo and stabilized on sirolimus FEV1 slope was -12±2 ml/mo. (placebo) vs. 1±2 ml/mo. (sirolimus) *p<0.0001

  25. FEV1 stabilized on sirolimus while treatment continued and declined in parallel with the placebo group when drug was stopped

  26. At the end of the treatment period, FEV1 stabilized or improved for 46% of patients on sirolimus vs. 12% on placebo *p<0.001

  27. 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

  28. 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

  29. 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)

  30. MILESIndividual FVC curves for 89 subjects

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

  32. MILESFVC fell in patients on placebo and improved on sirolimus p<0.001

  33. At the end of the treatment period, FVC was at or above baseline for 54% of patients on sirolimus, compared to 23 % on placebo p<0.001

  34. 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

  35. 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. ClinExperRheumatol 2010

  36. 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 placebo RV FRC TLC * sirolimus *p=0.049

  37. Sirolimus resulted in an increase in the slope of the Functional Performance Inventory and Quality of Life visual analogue scale score * *p=0.03

  38. Sirolimus resulted in an increase in the slope of the Functional Performance Inventory score * *p=0.03

  39. Serum VEGF-D was stable in the placebo group and declined on sirolimus *P<0.001 at 12 months

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

  41. 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)

  42. 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

  43. 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

  44. 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

  45. Adverse events • Most common • Mouth ulcers • Diarrhea • Nausea • Elevated cholesterol • Acne-like rash • Lower extremity swelling

  46. MILESPneumothorax

  47. MILESRelatedness of serious adverse events

  48. 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

  49. Compared to subjects in the LAM Registry, lung function impairment was more severe in MILES subjects % predicted Ryu et al. AJRCCM 173:105, 2006

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