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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 • • • • 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 • • • • 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 • • • • • 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 • • • • • 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 – – – – 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..) • • • • 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 – – – – – – – 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 • • • • • 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 • • • • • Asymptomatic metastatic HRPC 612 patients in 2 studies Atrasentin may slow growth of cancer Reduction in bone pain Reduction in bone destruction