Transcript A Phase III, Randomized, Double-Blind, Placebo

A Phase III, Randomized,
Double-Blind, PlaceboControlled Study of the safety and
Efficacy of 10 mg Atrasentan in
Men with Metastatic, HormoneRefractory Prostate Cancer
Dr. Howard GURNEY
Dept. of Medical Oncology and Palliative
Care
Westmead Hospital
WESTMEAD NSW 2145
Atrasentan
studies cancer
Advanced
prostate
‘Phase’
Hormone
Sensitive
Hormone
Resistant
No Symptoms
Symptoms
Symptoms
PSA
Treatment
Hormone therapy
Eg zoladex, lucrin,
orchidectomy
Cosudex, androcur
No therapy
available
Radiotherapy,
Strontium
Chemotherapy
Experimental drugs
How Atrasentan works
Prostate
Cancer Cell
Endothelin A
receptor
Endothelin 1
How Atrasentan works
Prostate
Cancer Cell
Endothelin A
receptor
+
Cancer growth
How Atrasentan works
Prostate
Cancer Cell
Endothelin A
receptor
+
Cancer growth
endothelin
atrasentan
Atrasentan
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Tablet
10mg
Soft-gelatin capsule
Taken once daily
Atrasentan studies so far
• Over 600 patients treated
• Phase 1 studies - safe
• Phase 2 studies
– May delay growth of prostate cancer
– May delay onset of bone pain in patients with
bone deposits of prostate cancer
• Phase 3 study - this study
– Confirm that atrasentan is effective
Description
• Placebo Controlled
• 1000 men internationally
• Randomization
• Double-Blinded
• Hormone resistant
• Minimal or no symptoms from cancer
Artasentan - side effects
• Common
Headaches
nasal congestion
swelling of the legs
Artasentan - side effects
• Uncommon
decreased blood pressure
shortness of breath
increase in weight
low red blood cell count
irritation and redness of the eyes
dizziness
• Rare
infection and heart failure
Artasentan - side effects
Anaemia
Loss of appetite
Bone pain
Constipation
Breathlessness
Headache
Infection
Nausea
Leg swelling
Rash
Rhinitis
Placebo
12%
14%
40%
12%
3%
12%
4%
12%
19%
5%
12%
Atrasentan
19%
12%
30%
22%
13%
23%
7%
21%
39%
10%
28%
Who is this study suitable for?
• Prostate cancer treated with
orchidectomy or
Zoladex or
Lucrin
• Cancer progressing (rising PSA)
• Cancer is resistant to hormone therapy
Aims
• To test whether Atrasentan will
1. slow the growth of the cancer
2. Delay onset of symptoms
3. Reduce complications of the cancer
4. Extend life
3 studies
• 1. Evidence of distant spread eg bone,
lymph node
• 2. No evidence of spread from prostate
(but hormone-resistant)
• 3. Extension study - if patient has
progressed or completed other 2 studies
Eligibility
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Hormone resistant Prostate cancer
Stopped hormone tablets
Continue Zoladex or Lucrin
PSA greater than 20 or
Two sequential PSA rises above 5 (2 weeks apart)
eg PSA = 6.3
7.8
Eligibility
• No previous radiotherapy to
bone(radiotherapy to prostate allowed)
• No previous chemotherapy
• No previous morphine or strong pain killers
for prostate cancer
Eligibility
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•
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No other cancer within 5 years
Good ‘performance score’
Good liver and kidney function (blood tests)
Must use latex condom
No unstable heart or lung disease
Design
Placebo arm
Consent
tests
Monitor
18 months
Atrasentan
Cancer
progression
Atrasentan
Atrasentan arm
Study Drug
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Tablet- Placebo or Atrasentan
Once d aily at the same time
Soft-gelatin capsule
Bottle of 45 capsules
Patient, doctor, nurse, company monitor’s will be
‘blinded’
• Unblinding only occurs if
– Medical emergency
– After study completed - all patients finished study
Cancer progression
• Pain due to cancer needing
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Morphine
Steroids
Radiotherapy
Chemotherapy
• Bone fracture
• Other evidence of cancer progression on CT scan
• Bone scan showing 2 or more new bone lesions
• NB - Rise in PSA alone is NOT considered cancer
progression
What is Involved
• We will determine if this study is suitable for you.
• Further tests and procedures will be necessary to
determine suitability
Bone Scan
CT Scan
ECG,
blood tests
Visits
• Will need to return for visits with the study
nurse or doctor on
Week 2
Week 4
Week 8
Week 12
Then every Six weeks for 12 months
Visits Schedule
• Every visit
Physical examination
Blood pressure
Weight,
Blood samples (2-4 Teaspoons)
Urine
Questionnaire to measure Quality of Life
Visits Schedule
• Every 3 months
• full body bone scan.
• CT Scan and MRI only done again if
changes found on the initial Scans.
Visits (Cont..)
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Initial Screening visit may take 4 Hrs
Subsequent visits will take 1 - 1.5 Hrs
Max. 13 visits over 12 months
After study is completed - Every 3 months
Can other medication be used?
• Any medications that you normally take can be
continued
• You may not take
– Steroids (prednisone, dexamethasone, cortisone)
– Hormone tablets (cosudex, androcur, PC-SPES,
eulexin, anandron etc)
• Bisphosphonates (alendonate, fosomax,
clodronate, bonefos etc)
Blood pressure tablets
• If you are on blood pressure tablets
– your BP should be checked by your GP 1 week after
starting on the study
– You should see your GP regularly for BP check
– Your BP tablets may need to be reduced
Risks to fetus
• Causes birth defects in fetus.
- Not recommended if planning to have a baby
• Two forms of birth control must be used
during the study and for eight weeks after
the end of the study.
– One form must be a Latex condom
Conclusion
• Study is voluntary
• no payment to take part in the study, but
reasonable travel expenses will be
reimbursed.
• Study drug, doctors visits, procedures and
laboratory tests performed only for this
study will be provided without charge.
Consent
• You may withdraw from the study at any
time for any reason
• Standard alternative therapy will be offered,
if available
Thank you for your attendance
• Study 1 ( Metastases)
• Study 2 (no metastases)
starts after 13th August
starts end of September
• If you are interested in the study let
Junie McCourt know 98457031
Or
Dr Gurney at next consultation
Endothelin axis
• Endothelin peptides (ET-1, ET-2, ET-3)
• Endothelin receptors (ETA, ETB)
• ET-1 circulating form, produced by
endothelial cells and prostate epithelium.
• ET-1 over-expressed in prostate cancer
• ET-1 levels higher in HRPC
• ETB - normal prostate
• ETA - prostate cancer
Endothelin-A receptor
• ETA - endothelin 1 is ligand
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increases with increasing grade
Increased in prostate cancer, kidney, breast, colon
Vasoconstriction
Proliferation of cancer cells
Anti-apoptotic
Bone remodelling (ETA on osteoblasts - ALP, matrix)
Causes pain
Atrasentan
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Selective, potent ETAR antagonist
T1/2 25 hours
Oral
No direct affect on PSA production
21 phase 1 and 2 studies in healthy
volunteers, prostate and other cancers,
diabetic nephropathy and CCF
Atrasentin in prostate cancer
• Dose limiting toxicity in healthy volunteers
is headache
– Rhinitis, peripheral oedema, dyspnoea
• Reduction in pain at 11 weeks in 419 pts
with bone mets
• Reduction in bone destruction
Atrasentan in prostate cancer
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Asymptomatic metastatic HRPC
612 patients in 2 studies
Atrasentin may slow growth of cancer
Reduction in bone pain
Reduction in bone destruction