The Multicenter International LAM Efficacy of Sirolimus Trial MILES Trial

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• The Multicenter International LAM Efficacy of
  Sirolimus Trial (MILES Trial)
• Frank McCormack, M.D.
• Scientific Director, The LAM Foundation
• Professor and Director, Division of Pulmonary,
  Critical Care and Sleep Medicine
• The University of Cincinnati

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Treatments for LAM in 2008

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Compared to other diseases that scar the lung,
LAM has several assets

• We understand a lot about the cause of LAM
• We have many ideas for drugs to test based on
  sound science
• LAM science is moving as quickly as any in
  pulmonary medicine
• We have a motivated, intelligent, organized
  patient population

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State of the science for lung fibrosis compared
to LAM
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Finding an effective treatment for LAM

• Carefully conducted clinical trials are the
  fastest and safest way to find treatments that
  work in people and ways to improve health.

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Examples of diseases that can be controlled and
sometimes cured because clinical trials were done
properly

• AIDS
• Leukemias
• Lymphomas
• Breast cancer

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Clinical trials

• Clinical trials often pose risk

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Renal AMLs shrunk by 50 on sirolimus, but tended
to return to baseline off drug
Bissler et. al NEJM 2008 358 140-51
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FEV1 and FVC increased on sirolimus, and then
resumed decline when the drug was stopped
FVC, CAST
FEV1, CAST
FVC, NIH Registry
N 11
FEV1, NIH registry
Bissler et. al NEJM 2008 358 140-51
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Parameters that did not change in CAST

• Diffusing capacity for carbon monoxide
• Total lung capacity
• Six minute walk distance

Bissler et. al NEJM 2008 358 140-51
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Adverse events

• There were six serious adverse events (I.e.-with
  hospitalization) probably or possibly related to
  sirolimus
• Diarrhea
• Community acquired pneumonia
• Pyelonephritis
• Cellulitis
• Stomatitis
• Hemorrhage into AML
• Aphthous ulcers in 17/23 patients
• Hyperlipidemia in 13/23 patients

Bissler et. al NEJM 2008 358 140-51
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What is sirolimus?

• Sirolimus (also known as rapamycin) is a drug
  that is FDA approved for kidney transplant
  patients.
• Sirolimus suppresses the immune system, and helps
  to prevent rejection.
• Sirolimus inhibits cell growth and has activity
  against some tumors

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Why was sirolimus chosen for the first LAM
clinical trial?

• Sirolimus has been tested in the lab against
  LAM-like cells and in experimental animals that
  have LAM-like features
• Sirolimus has been tested in LAM patients in a
  pilot study, called the Cincinnati Angiomyolipoma
  Sirolimus Trial (CAST)

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Theory for use of sirolimus in LAM

• Our theory is that sirolimus will restore orderly
  growth and movement to LAM cells, so that they
  stop multiplying, and invading and damaging the
  lung

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Major objective of the MILES Trial

• To determine if sirolimus has a beneficial effect
  on lung function

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Who is sponsoring the MILES Trial?

• National Institutes of Health
• NCRR (National Center for Research Resources)
• NHLBI (National Heart Lung and Blood Institute)
• The LAM Foundation
• The Tuberous Sclerosis Alliance
• Wyeth Pharmaceuticals
• The Adler Foundation

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Geographic Distribution of Sites in The MILES
Trial
Toronto
Osaka
Osaka
Osaka
Niigata
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MILES Lead Personnel

• FDA IND Sponsor/Principal Investigator
• Frank McCormack, M.D.
• Co- Investigator
• Brent Kinder, M.D., Lisa Young, M.D.
• Project Manager/Regulatory Leslie Korbee
• Senior Study Monitor Elva Turner, CCRC
• Lead Study Coordinator Susan McMahan, RN
• PFT Consultant Roy McKay, PhD
• Radiology Consultant Cris Meyer, M.D.
• Investigational Pharmacist Denise LaGory, RPh
• Central Laboratory Lori Davis

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Am I eligible for MILES?

• You must be 18 or over and able to consent for
  yourself
• You must have a definite diagnosis of LAM by
• CAT scan
• and
• either a biopsy or known tuberous sclerosis,
  angiomyolipoma or chylothorax or Serum VEGF-D
  greater than 800 pg/ml

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Am I eligible for MILES?

• Lung function must be abnormal
• FEV1 must be equal to or less than 70 of
  predicted (postbronchodilator)
• for statistical power, there needs to be the
  capacity for improvement on the drug

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Am I eligible for MILES?

• You should not enroll in MILES if you are, or
  will soon be, active on a lung transplant list
• You cannot enroll in MILES if you have a large
  collection of chyle in your chest or abdomen that
  may interfere with pulmonary function tests

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Am I eligible for MILES

• Other exclusions
• Recent cancer (except skin or cervix)
• Angina or prior heart attack
• Recent surgery
• Ongoing infection, including Hep C

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Who is eligible for MILES?

• Eligibility is determined from the history and
  tests performed on the first visit
• Patients who are eligible and willing are
  assigned a treatment by randomization.

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The MILES Trial is

• Placebo-controlled
• Some patients get sirolimus 2 milligrams and some
  patients get a placebo (sugar pill)
• Randomized
• The computer flips a coin to determine who gets
  placebo or sirolimus
• Double-blind
• neither the doctor or the patient knows who is
  taking the drug or the placebo

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MILESWhy does there have to be a placebo arm?

• Without a placebo, it is very easy to be fooled.
• pulmonary test results vary with how hard
  patients try
• patients who are hopeful they are on an effective
  drug may try harder

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How many patients will be enrolled in the MILES
trial

• 120 total
• 60 in the placebo arm
• 60 in the sirolimus arm

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MILESTime in the trial

• Each MILES subject spends two years on the study
• The first year is on the drug or placebo and the
  second year is off treatment.

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MILESWhat will be expected of me?

• 8 visits over 2 years
• The first visit is two days long.
• All other visits are one day long.
• Pulmonary function tests, questionnaires and
  blood tests are done on all visits
• Chest xrays are done at the beginning and the end
• CAT scans of the chest are done at the beginning,
  middle and the end

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MILESWhat will be expected of me?

• Sirolimus levels will be performed on all visits
  after the first one. Levels are not revealed to
  your study team.
• Urine pregnancy tests are done at every visit and
  3 months after the drug or placebo is stopped.

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MILES Schedule of Events
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Sirolimus Side Effects

• Mouth ulcers
• High cholesterol
• Lung inflammation
• Low platelets
• Acne-like lesions
• Diarrhea
• High blood pressure

• Protein in the urine
• Suppression of the immune system
• Swelling
• Hypertension
• Skin cancer
• Latent malignancy
• Death

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MILES

• How is patient safety ensured?
• Adverse events are reviewed by
• the principal investigator
• a study monitor
• a Data and Safety Monitoring Board
• the FDA
• The patient can withdraw consent at any time
• The investigator can remove the patient from the
  study at any time

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The interim analysis

• When40- 50 patients (25 in each arm) reach the 1
  year point, an analysis will be done.
• If sirolimus is proven to be of benefit, all
  patients will cross into the sirolimus arm.
• If sirolimus appears to impair lung function, or
  to cause harm, the study will be interrupted and
  the Data and Safety Monitoring Board will conduct
  a review

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The final analysis

• The final analysis will occur when all patients
  complete their two years on study.
• Since it may take a year or more to recruit all
  subjects, MILES will take at least 3 years to
  complete.

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If MILES shows that sirolimus has a positive
effect on lung function, what is next?

• Determine if sirolimus has a beneficial effect on
  exercise tolerance, survival and quality of life.
• Determine the minimum effect dose
• Determine if therapy should be one time,
  intermittent or continuous
• Determine if combination therapies with other
  drugs may be even more effective.

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If MILES shows that sirolimus is not effective,
what is next?

• Sirolimus or another drug like it may be tested
  using other trial designs
• Other drugs and targets may be explored
• metalloproteinase inhibitors
• angiogenesis/lymphangiogenesis inhibitors
• statins
• selective estrogen antagonists
• aromatase inhibitors
• farnesyl transferase inhibitors
• tyrosine kinase inhibitors

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What trials other trials are currently enrolling?

• UK doxycycline trial
• Multicenter Angiomyolipoma RAD Trial

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What other trials are being discussed

• Lipitor (Atorvastatin)
• Lymphangiogenesis inhibitors (anti-VEGF-D)
• Selective estrogen antagonists (SERMS)

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How can I learn more about MILES?

• Review materials and register at
  www.rarediseasesnetwork.org
• Go to the LAM Foundation Website
  www.thelamfoundation.org
• Write an email to milestrial_at_cchmc.org
• Call or write to your local MILES team

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Site physician investigators

• Cincinnati Frank McCormack, MD
• Portland Alan Barker, MD
• NIH Joel Moss, MD, PhD
• Cleveland Clinic Jeffrey Chapman, MD
• Gainesville Mark Brantly, MD, PhD
• Charleston Charlie Strange, MD
• Denver Kevin Brown, MD
• Tyler James Stocks, MD
• UCLA Joseph Lynch, MD
• Osaka/Niigata Yoshikazu Inoue/Koh Nakata
• Toronto Lianne Singer MD
• Boston Hilary GoldbergMD

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How to explore participation in MILES

• Contact the research coordinator at your local
  site.
• A consent form will be mailed to you to read
  before you visit the site.
• The site investigator will explain the risks and
  benefits of the study to you.
• To enroll, you must sign the consent in the
  presence of the site personnel

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Cincinnati team

• Project manager
• - Leslie Korbee
• Trialwide coordinator
• Susan McMahan
• Trialwide monitors
• Elva Turner
• Rubina Dosani

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Site phone numbers and emails
Frank.McCormack_at_uc.edu 513-558-4831

• Cincinnati MILEStrial_at_cchmc.org 513-636-6272
• Portland barkera_at_ohsu.edu 503-494-7680
• NIH mhaughey_at_nhlbi.nih.gov 301-644-5864
• Cleveland Clin failed_at_ccf.org 216-444-9975
• Gainesville pschreck_at_ufl.edu 352-294-0512
• Charleston gitterac_at_musc.edu 843-792-3161
• Denver morrisonm_at_njc.org 303-398-1912
• Tyler jan.hoeft_at_uthct.edu 903-877-5518
• UCLA sgolleher_at_mednet.ucla.edu 310-794-7093
• Osaka/Niigata giichi_at_kch.hosp.go.jp 81-72-252-302
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• Toronto lianne.singer_at_toronto.edu 416-340-4591
• Boston hjgoldberg_at_partners.org.
  617-732-7420