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ZOLEDRONIC ACID (ZOMETA R )

ZOLEDRONIC ACID (ZOMETA R ). FOR BONE METASTASES OF SOLID TUMOURS By Joan Fabbro BSc Pharm BCCA- Fraser Valley Center. Outline Bone metastases and cancer Bisphoshphonates in cancer Zoledronic acid Hypercalcemia Bone metastases Cost comparison Summary.

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ZOLEDRONIC ACID (ZOMETA R )

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  1. ZOLEDRONIC ACID (ZOMETAR) FOR BONE METASTASES OF SOLID TUMOURS By Joan Fabbro BSc Pharm BCCA- Fraser Valley Center

  2. Outline • Bone metastases and cancer • Bisphoshphonates in cancer • Zoledronic acid • Hypercalcemia • Bone metastases • Cost comparison • Summary

  3. Bone Remodelling in Healthy vs. Cancer Patients osteoclast = bone resorbing cells => osteolysis osteoblast = bone forming cells => osteogenesis Healthy bone “remodelling”: osteoclast = osteoblast activity

  4. Net bone resorbtion Release of growth factors => tumour growth Cancer Bone “remodelling”OsteolyticOsteoclast > Osteoblast Release mediators => stimulate osteoclast activity

  5. Osteogenic Osteoblast > Osteoclast Net bone formation Osteoclast activity osteolysis

  6. The Impact of Metastatic Bone Disease

  7. Bisphosphonates in cancer • 1) hypercalcemia • 2) bone mets • treatment • prevention-mixed evidence • Available in Canada : • Clodronate(BonefosR)…oral/IV • Pamidronate(ArediaR)…IV • Alendronate(FosamaxR)..oral • Etidronate(DidronelR , DidrocalR )..oral • Risendronate(ActonelR)….oral • Zoledronic Acid(ZometaR)…IV

  8. Bisphophonates - Mechanism of Action • clinical benefit takes several days • vs. osteoclast: • inhibit hyperactivity • inhibit maturation • inhibit attachment to bone site • decrease cytokine production • vs. tumour activity: • inhibit tumour cell invasion, proliferation & • adhesion to bone • induce apoptosis • reduce tumour cell proliferation

  9. Properties of bisphosphonates • Side Effects • flu-like symptoms • bone pain • GI complaints • dyspnea • lower limb edema Absorption • Low oral bioavailability • dose = side effects • Food Elimination • renal • bound to bone

  10. C Zoledronic Acid • New highly potent 3rd generation bisphosphonate • Heterocyclic nitrogen-containing molecule with: • A core bisphosphonate moiety • An imidazole-ring side chain containing 2 critically positioned nitrogen atoms Green JR, et al. JBone Miner Res. 1994;9:745-751.Green JR, et al. Pharmacol Toxicol. 1997;80:225-230.

  11. C Efficacy in Hypercalcaemia of Malignancy 87% P = .015* 82.6% P = .005* 70% Complete responders (%) 64% 45% 33% Major, P et al. JCO ,2001;19: 558-567

  12. Protocol • Design • Patients • Treatments • 010 • Randomized, double-blind, non-inferiority • Duration: 12 months • Multiple myeloma or breast cancer with bone metastases stratification: myeloma; breast Ca-chemo; breast Ca-hormonal • Zoledronic Acid 4mg, 8mg or pamidronate 90mg • 011 • Randomized, double-blind, placebo control • Duration: 9 months • Lung and other cancers with bone metastases (excluding breast or prostate) stratification: lung Ca; ‘other solid tumours’ • Zoledronic Acid 4mg, 8mg or placebo • 039 • Randomized, double-blind, placebo control • Duration: 15 months • Prostate cancer with bone metastases stratification: Prostate Ca - no mets; prostate Ca with mets • Zoledronic Acid 4mg, 8mg or placebo • 10 efficacy parameter: proportion of patients with at least one skeletal-related event (SRE) • Adjustments: zoledronic acid infused over 15 min. 8mg dose => 4mg for renal complications PhaseIII Trials With Zoledronic Acid in Patients With Metastatic Bone Disease

  13. Protocol 010 Rosen L S, et al. Zoledronic Acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesiona of multiple myeloma: a phase III, double-blind commparative trial. Cancer J.2001; 7: 377-387

  14. Protocol 010 • Multicenter, double-blind, randomized, controlled, phase III • “inferiority” trial • Zoledronic Acid 4mg, 8mg IV vs. pamidronate 90 mg IV q 3-4 weeks x 12months • multiple myeloma, breast Ca (chemo, hormonal) • pamidronate 90 mg IV - standard • study objective: zoledronic acid non-inferior vs. pamidronate preventing SRE • 60% completed trial

  15. Breast Cancer and Multiple Myeloma proportion (%) of patients in protocol 010 With an SRE p= 0.052 N = 561 555 • Zoledronic Acid 4 mg versus pamidronate 90 mg: 95% CI (–7.9%, 3.7%). The noninferiority criterion, the upper boundary of the 95% CI, is below 8%

  16. 14 Protocol 010: Breast Cancer and Multiple Myeloma time to first SRE 010 PTF 9.2-1p4; CSR 010 T9-3 Median time, days Zoledronic Acid 4 mg 373 Pamidronate 90 mg 363

  17. Study 010 Comments (at 25 months) • 12 month extension N=606 (<40%) and >50% completion • % patients - one SRE (not HCM); Z4mg 47%;Pam90mg 51% • median time to first SRE - Z4mg 376 days; • Pam90mg 356 days • confirmed long-term safety, efficacy - ZoledronicAcid 4mg; • Pamidronate 90 mg • subset group (breast Ca-hormonal) - further trials

  18. Protocol 011 Rosen L, Gordon D, Tchekmedyian S, et al. Zoledronic Acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumours: A phase III, double-blind, randomized trial - the Zoledronic acid lung cancer and other solid tumours study group. JCO 21: 3150 - 3157, 2003.

  19. Protocol 011 • Randomized, double-blind, multicenter, phase III • placebo control trial • zoledronic Acid 4mg, 8mg IV vs. placebo q3weeks (daily calcium/vit D) x 9 months • bone metastases from solid tumours • not breast or prostate • study objective: efficacy- zoledronic acid+chemo vs. chemo preventing SRE • 25 % completed trial

  20. 12 Protocol 011: Solid tumors (not PC &BC) proportion (%) of patients with an SREtime to first SRE P = .127 N = 257 N = 250 Median time, days P-value Zoledronic Acid 4 mg 230 .023 Placebo 163

  21. Protocol 039 Saad F, et al. Journal of the National Cancer Institute. 2002; 94 : 1458 - 1468.

  22. Protocol 039 • Randomized, double-blind, multicenter, phase III • placebo control trial • zoledronic acid 4mg, 8mg IV vs. placebo q 3 weeks (daily calcium/vit D) • 15 months • prostate cancer - metastatic, PSA, hormonal treatment • study objective: efficacy zoledronic acid+chemo vs chemo preventing SRE • 40 % completed trial

  23. Zoledronic Acid 4 mg Placebo Proportion of protocol 039 patients with skeletal-related events (SRE) 0.8 0.7 0.6 0.5 Proportionof patients p = 0.021 0.4 0.3 44.2% 33.2% 0.2 0.1 0 All patients Saad F, et al. Journal of the National Cancer Institute. 2002; 94 : 1458 - 1468.

  24. Protocol 039: Time to first skeletal-related event Median Time: Zoledronic Acid 4 mg=NR Placebo = 321 days 100 90 80 70 60 50 40 30 20 10 0 Percent of patients without event P-value = 0.011 0 50 100 150 200 250 300 350 400 450 500 550 Time after start of therapy (days) NR = not reached Saad F, et al. Journal of the National Cancer Institute. 2002

  25. Subset Analysis of Renal Cancer Patients from • Study 011 • N= 74 pt • 10 endpoint - 74% placebo vs 37% Zoledronic Acid • the time to SRE & morbidity rate - improved significantly • on the zoledronic acid 4mg arm. • bone pain - placebo group • subset group = lower numbers = lower power • warrants investigation • delaying onset of SRE in renal Ca patients

  26. Cost Comparison Pamidronate vs Zoledronic Acid • Pamidronate 90 mg (monthly cost) $307.35 • Zoledronic Acid 4mg (monthly cost) $564.63 • chair time shorter for Zoledronic acid (15 min vs 1-2 hours • infusion ) • time/motion study in USA - adapted to Canada • Zoledronic Acid $9 more expensive to administer • IV zoledronic acid vs. IV pamidronate = 1 hr extra chair time Dranitsaris, G et al. Zoledronic Acid versus pamidronate as palliative therapy in cancer patients: A Canadian time and motion analysis. J Oncol Pharm Practice 2001;7: 27 - 33

  27. Summary • cancer mets to bone => morbidity • bisphosphonates provide clinical benefit • Zoledronic Acid more effective than pamidronate in • hypercalcemia of malignancy and shorter infusion time • study 010 suggests zoledronic acid 4mg IV effective in • patients with bone mets from breast cancer/multiple myeloma • studies 011 and 039 support efficacy of zoledronic acid 4mg • IV vs. placebo in pts with bone mets from solid tumours • renal subset analysis of study 011 numbers and power

  28. BCCA - Benefit • Current: • multiple myeloma - pamidronate • breast Ca + mets - clodronate • Future: • (PEC proposal) • prostate Ca + mets - zoledronic acid • renal Ca - zoledronic acid

  29. BCCA - Non benefit • Current: • hypercalcemia - pamidronate • palliative care - pamidronate • - zoledronic acid • Future: • prostate Ca osteoporosis • + LHRH - zoledronic acid

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