zometa hcm slide kit

Hypercalcemia of malignancy: Current clinical perspectives

Pathogenesis of HCM

Types of HCM

Signs and symptoms of HCM

Diagnosis of HCM

Overview of treatment of HCM

ZOMETA™ (zoledronic acid for injection)

Overview of hypercalcemia of malignancy (HCM)

Pathogenesis of HCMPathogenesis of HCM

Mechanisms of HCMMechanisms of HCM11

■ Increased bone destructionIncreased bone destruction

■ Increased tubular reabsorption of calcium by the kidneyIncreased tubular reabsorption of calcium by the kidney

■ Decreased urinary calcium excretionDecreased urinary calcium excretion

■ Decrease in bone formationDecrease in bone formation

1. Fleisch H. In: Bisphosphonates in Bone Disease. San Diego, California: Academic Press; 2000;90-92.

1. Mundy GR. (ed). Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin Dunitz Ltd; 1999;107-122. 2. Mundy GR. Hosp Pract. 1999;81–94.

Pathogenesis of HCMPathogenesis of HCM

Factors involved in HCMFactors involved in HCM1,21,2

■ PTHrPPTHrP

■ Bone-resorbing cytokines (TGFs, TNFs, IL-1)Bone-resorbing cytokines (TGFs, TNFs, IL-1)

■ 1,25 (OH)1,25 (OH)22 D D

■ ProstaglandinsProstaglandins

Factors involved in HCMFactors involved in HCM

Parathyroid hormone-related protein (PTHrP) Parathyroid hormone-related protein (PTHrP)

■ Produced by tumor cellsProduced by tumor cells1,21,2

■ Stimulates vicious cycle of osteoclastic bone resorption Stimulates vicious cycle of osteoclastic bone resorption contributing to HCMcontributing to HCM1,21,2

■ Also stimulates increased renal tubular calcium resorptionAlso stimulates increased renal tubular calcium resorption1,31,3

1. Goltzman D, Kremer R, Rabbani SA. Molecular basis of the spectrum of skeletal complications of malignancy. Abstract presented at the SecondNorth American Symposium on Skeletal Complications of Malignancy. October 15–16, 1999; Montréal, Canada. 2. Guise TA. Molecular mechanismsof osteolytic metastases. Abstract presented at the Second North American Symposium on Skeletal Complications of Malignancy. October 15–16,1999; Montréal, Canada. 3. Mundy GR (ed). Bone Remodeling and Its Disorders. London, England: Martin Dunitz Ltd; 1989;113-119.


Bone-resorbing cytokines Bone-resorbing cytokines

■ Four types exhibit potent bone-resorbing activityFour types exhibit potent bone-resorbing activity

— Transforming growth factors (TGF-Transforming growth factors (TGF-∝∝ and TGF- and TGF-ββ ))11

— Tumor necrosis factors (TNF-Tumor necrosis factors (TNF-∝∝ and TNF- and TNF-ββ ))2,32,3

— Colony-stimulating factors (CSFs)Colony-stimulating factors (CSFs)22

— InterleukinsInterleukins44

1. Todaro GJ, Fryling D, DeLarco JE. Proc Natl Acad Sci USA. 1980;77:5258-5262. 2. Mundy GR (ed). Bone Remodeling and Its Disorders. London, England: Martin Dunitz Ltd; 1989;45-82; 113-119. 3. Mundy GR. Endocrinol Metab Clin North Am. 1989;18:795-806. 4. Kelly PJ, Eisman JA. Cancer Metastasis Rev. 1989;8:23-52.


1,25 (OH)1,25 (OH)22 D D11

■ Increased production by tumor cells leads to HCMIncreased production by tumor cells leads to HCM

■ Increased production leads to increased serum calcium levels viaIncreased production leads to increased serum calcium levels via

— Recruitment of osteoclast precursorsRecruitment of osteoclast precursors

— Production of osteoclast-stimulating factors from osteoblastsProduction of osteoclast-stimulating factors from osteoblasts

1. Mundy GR. (ed). Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin Dunitz Ltd; 1989;45–82; 113-119.


Prostaglandins Prostaglandins

■ Involved in regulatory functions throughout the bodyInvolved in regulatory functions throughout the body

■ Associated with pain and inflammationAssociated with pain and inflammation

■ Role in HCM is unclearRole in HCM is unclear

— Possible bidirectional effect on osteoclastsPossible bidirectional effect on osteoclasts11

– transient effect to slow bone resorptiontransient effect to slow bone resorption

– sustained effect to increase bone resorptionsustained effect to increase bone resorption

— Could be produced by host immune cells in response to tumorCould be produced by host immune cells in response to tumor

1. Mundy GR (ed). Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin Dunitz Ltd; 1999;56-59, 118.

Types of HCMTypes of HCM

Humoral hypercalcemia of malignancyHumoral hypercalcemia of malignancy

Local osteolytic hypercalcemia associated with bone metastasesLocal osteolytic hypercalcemia associated with bone metastases

Hypercalcemia associated with hematologic malignanciesHypercalcemia associated with hematologic malignancies


Humoral hypercalcemia of malignancy (HHM)Humoral hypercalcemia of malignancy (HHM)

1. Mundy GR. In: Mundy GR (ed). Calcium Homeostasis: Hypercalcemia and Hypocalcemia. 1990;69-99.

Adapted with permission from Mundy GR.1

Increased Ca reabsorptionInhibition of Pi reabsorptionIncreased cAMP excretion

Inhibition of Ca++ absorption

Stimulation of osteoclastic resorption

Inhibition of bone formation

Ca++


Local osteolytic HCM associated with bone metastasesLocal osteolytic HCM associated with bone metastases1-31-3

1. Guise TA, Mundy GR. Cancer and bone. Endocr Rev. 1998;19:18-54. 2. Mundy GR (ed). Cellular mechanisms of bone resorption. In: Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin Dunitz Ltd; 1999;23-25. 3. Mundy GR. Cancer. 1997;80 (suppl 8):1546-1556.

1 Metastatic tumor cells release factors—PTHrP, prostaglandin E, growth factors, and cytokines—that directly stimulate osteoclast activity1,2

2 Osteoclastic activity releases growth factors (ie, TGF-β) that stimulate tumor-cell growth, perpetuating a vicious cycle of bone resorption2

3 Bone resorption releases calcium from the skeleton, increasing the flow of calcium through the extracellular space, resulting in elevated serum calcium1

PTHrP

Tumorcells

Ca++ Ca++

Ca++

Osteoclast

2 Bone-derived growth factors (ie,TGF-ß)3 Ca++

1

Adapted with permission from Mundy GR, Guise TA, Place N.


Hypercalcemia associated with hematologic malignanciesHypercalcemia associated with hematologic malignancies

HCM in multiple myelomaHCM in multiple myeloma

■ Extensive destruction of bone adjacent to myeloma cellsExtensive destruction of bone adjacent to myeloma cells

■ Impaired glomerular filtration and excessive calcium load Impaired glomerular filtration and excessive calcium load exacerbate hypercalcemiaexacerbate hypercalcemia

HCM in malignant lymphomas and leukemiaHCM in malignant lymphomas and leukemia

■ Possibly mediated by tumor-produced factors that have Possibly mediated by tumor-produced factors that have bone-resorbing activitybone-resorbing activity

Signs and symptoms of HCMSigns and symptoms of HCM11

1. Morton AR, Lipton A. Clin Oncol. 1995;527-542. 2. Barnett ML. Semin Oncol Nurs. 1999;190-201.

CNSCNS Altered levels of consciousness; Altered levels of consciousness; lethargy; somnolence; stupor; coma; lethargy; somnolence; stupor; coma; depression; psychosis; ataxiadepression; psychosis; ataxia

NeuromuscularNeuromuscular Muscle weakness; proximal myopathy; hypertoniaMuscle weakness; proximal myopathy; hypertonia

CVCV Hypertension; bradycardia; shortened QT intervalHypertension; bradycardia; shortened QT interval

RenalRenal Kidney stones; decreased glomerular filtration; Kidney stones; decreased glomerular filtration; polyuria; acidosis; increase in corrected serum calciumpolyuria; acidosis; increase in corrected serum calcium

GIGI Nausea; vomiting; constipation; anorexiaNausea; vomiting; constipation; anorexia

SkeletalSkeletal22 Bone painBone pain

Diagnosis (Dx) of HCMDiagnosis (Dx) of HCM

Consider Dx in any person with cancer showing symptomatic Consider Dx in any person with cancer showing symptomatic deteriorationdeterioration11

Confirm by measuring corrected serum calcium (CSC)Confirm by measuring corrected serum calcium (CSC)2-42-4::

■ CSC, mg/dL = Serum Ca, mg/dL + 0.8 (4.0 – serum albumin, g/dL)CSC, mg/dL = Serum Ca, mg/dL + 0.8 (4.0 – serum albumin, g/dL)

1. Ralston SH. In: Body JJ (ed). Tumor Bone Diseases and Osteoporosis in Cancer Patients. New York, NY: Marcel Dekker; 2000;393-407. 2. Iqbal SJ, Giles M, Ledger S, Nanji N, Howl T. Lancet. 1988;ii:1477-1478. 3. Payne RB, Little AJ, Williams RB, Milner JR. BMJ. 1973;4:643. 4. Morton AR, Hercz G. Dialysis Transplant. 1991;20:661.

Overview of treatment of HCMOverview of treatment of HCM

Principles of antihypercalcemic treatmentPrinciples of antihypercalcemic treatment

■ Treatment of mild HCM (CSC levels ≥12mg/dL): Treatment of mild HCM (CSC levels ≥12mg/dL):

— Ambulation; avoid inactivity; avoid salt restriction and dehydration; Ambulation; avoid inactivity; avoid salt restriction and dehydration; force fluids; in lymphoma patients, restrict dietary calciumforce fluids; in lymphoma patients, restrict dietary calcium

■ Treatment of moderate HCM (CSC levels >12.8mg/dL) to severe HCM Treatment of moderate HCM (CSC levels >12.8mg/dL) to severe HCM (CSC levels >13.5mg/dL): (CSC levels >13.5mg/dL):

— Rehydration with intravenous fluid therapy to promote urinary Rehydration with intravenous fluid therapy to promote urinary excretion of calciumexcretion of calcium

— Antiresorptive drug therapy to inhibit osteoclastic bone resorptionAntiresorptive drug therapy to inhibit osteoclastic bone resorption


Treatment of moderate-to-severe HCM by rehydrationTreatment of moderate-to-severe HCM by rehydration11

■ Aggressively rehydrate with isotonic saline depending on Aggressively rehydrate with isotonic saline depending on cardiac statuscardiac status

■ Confirm good urine flowConfirm good urine flow

■ Loop diuretic, plus maintenance of volume expansionLoop diuretic, plus maintenance of volume expansion

— Match volume outputMatch volume output

— Monitor serum levels, and administer potassium and Monitor serum levels, and administer potassium and magnesium as necessarymagnesium as necessary

1. Barnett ML. Hypercalcemia. Semin Oncol Nurs. 1999;15(3):190-201.


Treatment of moderate-to-severe HCM by antiresorptive therapy Treatment of moderate-to-severe HCM by antiresorptive therapy

■ Salmon calcitoninSalmon calcitonin

■ Gallium nitrateGallium nitrate

■ IV bisphosphonate:IV bisphosphonate:

— Pamidronate disodium for injection: 4-to-24-hour infusionPamidronate disodium for injection: 4-to-24-hour infusion

— ZOMETA™ (zoledronic acid for injection): 15-minute infusionZOMETA™ (zoledronic acid for injection): 15-minute infusion

Treatment of moderate-to-severe HCM by Treatment of moderate-to-severe HCM by antiresorptive therapyantiresorptive therapy

Salmon calcitoninSalmon calcitonin11

■ Mechanism of actionMechanism of action

— AntiosteoclastAntiosteoclast

— Calciuric effectCalciuric effect

■ Dosage/route: 4–8 IU/kg IM or SC q6–12hDosage/route: 4–8 IU/kg IM or SC q6–12h

■ Side effects Side effects

— NauseaNausea

— VomitingVomiting

— Skin rashesSkin rashes

— Allergic reactionsAllergic reactions

1. Mundy GR, Martin TJ. Metabolism. 1982;31(12):1247-1277.

1. Warrel RP Jr. Gallium nitrate and bone metastases. In: Body JJ (ed). Tumor Bone Diseases and Osteoporosis in Cancer Patients. New York, NY: Marcel Dekker; 2000;483-492.


Gallium nitrateGallium nitrate11

■ Mechanism of actionMechanism of action

— Stabilizes bone crystalStabilizes bone crystal

— No morphologic cellular changesNo morphologic cellular changes

■ Dosage/routeDosage/route

— 200 mg/m200 mg/m22 body surface/day IV for 5 days body surface/day IV for 5 days

■ Side effectsSide effects

— Nephrotoxicity (hydrate, avoid aminoglycosides)Nephrotoxicity (hydrate, avoid aminoglycosides)

— Mild alkalosisMild alkalosis

■ ContraindicationsContraindications

— Renal insufficiencyRenal insufficiency


IV bisphosphonates for HCM IV bisphosphonates for HCM

■ The treatment of choice for HCM for reducing or The treatment of choice for HCM for reducing or inhibiting osteoclastic activityinhibiting osteoclastic activity

■ Available IV bisphosphonates for HCM:Available IV bisphosphonates for HCM:

— Pamidronate disodium for injectionPamidronate disodium for injection

— ZOMETA™ (zoledronic acid for injection)ZOMETA™ (zoledronic acid for injection)

ZOMETA™ (zoledronic acid for injection)ZOMETA™ (zoledronic acid for injection)

ZOMETA belongs to a new class of highly potent bisphosphonatesZOMETA belongs to a new class of highly potent bisphosphonates1,21,2

Heterocyclic, nitrogen-containing bisphosphonate composed of:Heterocyclic, nitrogen-containing bisphosphonate composed of:

■ A core bisphosphonate moiety A core bisphosphonate moiety

■ An imidazole-ring side chain containing 2 critically positioned An imidazole-ring side chain containing 2 critically positioned nitrogen atoms nitrogen atoms

1. Green J, et al. J Bone Miner Res. 1994;9(5):745-751. 2. Green J, et al. Pharmacol Toxicol. 1997;80(5):225-230.

1. Green J, et al. J Bone Miner Res. 1994;9(5):745-751.

Evaluation of potency of bisphosphonatesEvaluation of potency of bisphosphonates

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1. Green J, et al. J Bone Miner Res. 1994;9(5):745-751. 2. Evans CE, Braidman IP. Bone Miner. 1994;26:95-107. 3. Derenne S, et al. J Bone Miner Res. 1999;14:2048-2056. 4. Boissier S, et al. Cancer Res. 2000;60:2949-2954. 5. Marion G, et al. Bone. 1998;33:S379.

ZOMETA™ (zoledronic acid for injection) — ZOMETA™ (zoledronic acid for injection) — mechanisms of actionmechanisms of action

ZOMETA reduces bone resorption by potently inhibiting ZOMETA reduces bone resorption by potently inhibiting osteoclast hyperactivityosteoclast hyperactivity

Proposed mechanisms of action include:Proposed mechanisms of action include:

■ Functional suppression of mature osteoclastFunctional suppression of mature osteoclast11

■ Inhibition of osteoclast maturationInhibition of osteoclast maturation22

■ Inhibition of osteoclast recruitment to the siteInhibition of osteoclast recruitment to the site22

■ Reduction in the production of cytokines, eg, IL-1, IL-6Reduction in the production of cytokines, eg, IL-1, IL-633

■ Inhibition of tumor-cell invasion and adhesion to Inhibition of tumor-cell invasion and adhesion to bone matrixbone matrix4,54,5

ZOMETA™ (zoledronic acid for injection)—ZOMETA™ (zoledronic acid for injection)—product summaryproduct summary

Nitrogen-containing bisphosphonates are more potent Nitrogen-containing bisphosphonates are more potent inhibitors of bone resorptioninhibitors of bone resorption

ZOMETA has 2 nitrogens in an imidazole side-ring and ZOMETA has 2 nitrogens in an imidazole side-ring and is the most potent bisphosphonateis the most potent bisphosphonate

Zoledronic acid is a 100 to 850 times more potent inhibitor Zoledronic acid is a 100 to 850 times more potent inhibitor of osteoclasts than pamidronateof osteoclasts than pamidronate

ZOMETA™ (zoledronic acid for injection) vs ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection in HCMpamidronate disodium for injection in HCM

DesignDesign

■ Two randomized, double-blind, double-dummy, parallel-group Two randomized, double-blind, double-dummy, parallel-group trials of ZOMETA vs pamidronatetrials of ZOMETA vs pamidronate

■ 287 HCM patients287 HCM patients11

■ Single dose of ZOMETA (4 mg or 8 mg) as a 5-minute infusion, Single dose of ZOMETA (4 mg or 8 mg) as a 5-minute infusion, or a single 90-mg dose of pamidronate as a 2-hour infusionor a single 90-mg dose of pamidronate as a 2-hour infusion11

■ A planned pooled analysis of the data was conductedA planned pooled analysis of the data was conducted

Primary end point Primary end point

■ Comparative efficacyComparative efficacy

Secondary end pointSecondary end point

■ Comparative tolerabilityComparative tolerability

1. Major P, et al. J Clin Oncol. In press.


Patient demographicsPatient demographics11


SexMale n (%) 46 (53.5) 60 (66.7) 56 (56.6) 162 (58.9)Female n (%) 40 (46.5) 30 (33.3) 43 (43.4) 113 (41.1)

AgeMean years 60.0 58.7 59.0 59.0Range years 33–84 21–84 25–87 21–87

Primary cancer siteLung n (%) 15 (17.4) 25 (27.8) 23 (23.2) 63 (22.9)Breast n (%) 22 (25.6) 14 (15.6) 15 (15.2) 51 (18.5)Multiple myeloma n (%) 9 (10.5) 5 (5.6) 9 (9.1) 23 (8.4)Head and neck n (%) 9 (10.5) 9 (10.0) 12 (12.1) 30 (10.9)Renal n (%) 9 (10.5) 10 (11.1) 11 (11.1) 30 (10.9)Unknown n (%) 2 (2.3) 1 (1.1) 4 (4.0) 7 (2.5)Hematologic n (%) 9 (10.5) 7 (7.8) 7 (7.1) 23 (8.4)Other n (%) 11 (12.8) 19 (21.1) 18 (18.2) 48 (17.5)

ZOMETA4 mg

(N=86)

ZOMETA8 mg

(N=90)

pamidronate90 mg(N=99)

Total(N=275)Units


Patient demographicsPatient demographics1 1 (continued)(continued)


Bone metastasesNo n (%) 37 (43.0) 40 (44.4) 54 (54.5) 131 (47.6)Yes n (%) 49 (57.0) 50 (55.6) 45 (45.5) 144 (52.4)

Baseline PTHrP≤ 2 pmol/L n (%) 62 (72.1) 59 (65.6) 65 (65.7) 186 (67.6)>2 pmol/L n (%) 20 (23.3) 25 (27.8) 24 (24.2) 69 (25.1)

Bisphosphonate use in past yearNo n (%) 77 (89.5) 86 (95.6) 91 (91.9) 254 (92.4)Yes n (%) 9 (10.5) 4 (4.4) 8 (8.1) 21 (7.6)

ZOMETA4 mg

(N=86)

ZOMETA8 mg

(N=90)

pamidronate90 mg(N=99)

Total(N=275)Units


ZOMETA™ (zoledronic acid for injection) vs ZOMETA™ (zoledronic acid for injection) vs pamidronate disodium for injection HCMpamidronate disodium for injection HCM

Mean CSC by dayMean CSC by day11

13.95

11.04(P=.005)

10.08(P=.001)

9.96(P=.001)

13.96

11.47

10.63

10.59

8

10

12

14

16

Baseline Day 4 Day 7 Day 10

Corrected Day

ZOMETA 4 mg (N=86)

pamidronate 90 mg (N=99)

10.8

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Median duration of relapse of HCMMedian duration of relapse of HCM11


5 10 15 20 25

*(P=.001)

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17pamidronate 90 mg (N=99)

30*ZOMETA 4 mg (N=86)


Time to relapseTime to relapse11

ZOM 4 mg vs pam 90 mg: P=.001

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ZOMETA 4 mg — median 30 days

pamidronate 90 mg — median 17 days

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Complete response rateComplete response rate11::

Normalization of corrected serum calcium Normalization of corrected serum calcium ≤≤10.8 mg/dL (10.8 mg/dL (≤≤2.7 mmol/L)2.7 mmol/L)



ResultsResults11::

■ Significantly superior to pamidronate inSignificantly superior to pamidronate inthe treatment of HCMthe treatment of HCM11::

— Significantly faster normalization of corrected serum Significantly faster normalization of corrected serum calcium (calcium (PP≤≤ .05) .05)

— Significantly longer therapeutic effect (Significantly longer therapeutic effect (PP=.001)=.001)

— Significantly higher response rate (Significantly higher response rate (PP=.002)=.002)

■ Well tolerated at 4 mgWell tolerated at 4 mg

■ More rapid infusion than pamidronateMore rapid infusion than pamidronate



Summary—ZOMETASummary—ZOMETA

■ Highly effective in the treatment of HCMHighly effective in the treatment of HCM

■ ZOMETA 4 mg was more effective than pamidronate 90 mgZOMETA 4 mg was more effective than pamidronate 90 mg

■ 4-mg dose is recommended4-mg dose is recommended

ZOMETA™ (zoledronic acid for injection)—ZOMETA™ (zoledronic acid for injection)—AdministrationAdministration

Rapid administrationRapid administration

■ Recommended dose in HCM Recommended dose in HCM

— ZOMETA 4 mg via 15-minute infusionZOMETA 4 mg via 15-minute infusion11

1. Data on file. Novartis Oncology.

ZOMETA™ (zoledronic acid for injection)—ZOMETA™ (zoledronic acid for injection)—Safety and tolerabilitySafety and tolerability

Well tolerated, with a safety profile similar to that of pamidronateWell tolerated, with a safety profile similar to that of pamidronate

The most common treatment-related adverse experiences in clinical trialsThe most common treatment-related adverse experiences in clinical trials11

ZOMETA ZOMETA pamidronate pamidronateAdverse event 4 mg (N = 86) Adverse event 4 mg (N = 86) 90 mg (N = 99)90 mg (N = 99)

FeverFever 7.0%7.0% 9.7%9.7%

HypocalcemiaHypocalcemia 5.8%5.8% 1.9%1.9%

HypophosphatemiaHypophosphatemia 3.5%3.5% 1.0%1.0%

NauseaNausea 1.2%1.2% 1.0%1.0%

PruritusPruritus 1.2%1.2% 0% 0%

1. Data on file. Novartis Oncology.

HCM: Current clinical perspectives summaryHCM: Current clinical perspectives summary

Hypercalcemia of malignancy (HCM) is a serious and common Hypercalcemia of malignancy (HCM) is a serious and common metabolic complication of malignancymetabolic complication of malignancy

Consider the possibility of hypercalcemia in any person with cancer Consider the possibility of hypercalcemia in any person with cancer who starts to experience symptomatic deteriorationwho starts to experience symptomatic deterioration

Confirm diagnosis by measuring corrected serum calciumConfirm diagnosis by measuring corrected serum calcium

Tailor treatment to degree of hypercalcemia presentTailor treatment to degree of hypercalcemia present

IV bisphosphonates remain the treatment of choice for HCMIV bisphosphonates remain the treatment of choice for HCM

ZOMETA™ (zoledronic acid for injection) is a new, highly potent ZOMETA™ (zoledronic acid for injection) is a new, highly potent bisphosphonate that is significantly superior to pamidronate in the bisphosphonate that is significantly superior to pamidronate in the treatment of HCMtreatment of HCM11


zometa hcm slide kit

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