Download Protocol 010 - Virtual Medical Centre

Renal Safety of Zoledronic Acid in
Patients With Breast Cancer
2
ASCO Guidelines for Use of IV Bisphosphonates
in Breast Cancer
 Recommended for patients with
–
Evidence of bone destruction on plain radiographs
 Reasonable to initiate IV bisphosphonate therapy in
patients with bone destruction through imaging, but
who have normal plain radiographs
 Initiate IV zoledronic acid (4 mg via 15-minute
infusion) or pamidronate (90 mg via 2-hour infusion)
every 3 to 4 weeks
–
Oral bisphosphonates not recommended
Hillner B, et al. J Clin Oncol. 2003;21:4042-4057.
Zometa and Aredia Product Information
Major PP, et al. Cancer 88:6-14, 2000.
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ASCO Guidelines for IV Bisphosphonate
Use in Patients With Breast Cancer
 Once initiated, IV bisphosphonates should be
continued as long as tolerated or until evidence of
substantial decline in performance status
 Serum creatinine should be monitored before each
dose according to product information
 No changes in dose, infusion duration or interval is
necessary for patients with pre-existing renal disease
if serum creatinine is < 3.0 mg/dL (265 µmol/L)
Hillner B, et al. J Clin Oncol. 2003;21:4042-4057.
Zometa and Aredia Product Information
4
Recommendations for Zoledronic Acid
Treatment in Patients With Breast Cancer
 Zoledronic acid (4 mg) should be infused over no less than 15
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

minutes every 3 to 4 weeks
Withhold treatment for patients with
– Notable serum creatinine increase until it returns to within 10%
of baseline
Not recommended for patients with severe renal impairment:
– Creatinine levels > 400 micromol/L for patients with tumour
induced hypercalcaemia (TIH)
– Creatinine levels > 265 micromol/L for patients with bone
metastases
Ensure adequate hydration
Patients should also receive
– Oral calcium supplement of 500mg daily
– Multi-vitamin containing 400 IU of vitamin D daily
Zometa ® product information.
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Phase III Randomized Trial in Breast Cancer
and Multiple Myeloma (Study 010)

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
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
Stratification
–
Durie-Salmon stage III MM with  1 osteolytic bone lesion
–
Stage IV BC with  1 osteolytic, osteoblastic, or mixed metastatic
bone lesion
–
Patient stratification:
• those receiving chemotherapy (with or without hormonal
therapy)
• those receiving hormonal treatment
Appropriate antineoplastic therapy at baseline and during the course of
the trial
Baseline serum creatinine  3.0 mg/dL (265 µmol/L)
Patients randomized to zoledronic acid (4 or 8 mg) versus pamidronate
(90 mg) every 3 to 4 weeks for up to 24 months
Protocol amendments for renal safety
–
Increased zoledronic acid infusion time from 5 to 15 minutes
–
Reduced dose from 8 to 4 mg (8/4 mg group)
Rosen LS, et al. Cancer. 2003;98:1735-1744.
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Notable Serum Creatinine Increase
 Definition
–
Increase of > 44 micromol/L ( >0.5 mg/dL) in patients
with normal baseline serum creatinine (< 125
micromol/L/ < 1.4 mg/dL)
– Increase of > 88 micromol/L (>1.0 mg/dL) in patients
with abnormal baseline serum creatinine (≥ 125
micromol/L/  1.4 mg/dL/) or
– Doubling of serum creatinine from baseline value
 If serum creatinine was notably increased according to
above criteria, dose was held until serum creatinine
returned to within 10% of baseline
Rosen LS, et al. Cancer. 2003;98:1735-1744.
Zometa ® and Aredia product information.
Breast Cancer Patients*—Time to First Notable
Serum Creatinine Increase Was Similar in the
Zoledronic Acid and Pamidronate Groups
Kaplan-Meier Estimate of Time to First Notable Serum Creatinine Increase
Patients, %
100
80
60
40
20
Zol 4 mg
Pam 90 mg
0
0
Zol 4 mg
Pam 90 mg
181
184
n
Hazard ratio
181
184
1.401
P value
.371
120
240
360
480
600
Time after start of study drug, days
150
142
126
120
95
88
49
50
38
42
*Safety-evaluable patients treated post–15-minute infusion amendment.
Lipton A, et al. Presented at: 4th European Breast Cancer Conference.
2004: Poster 296.
720
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19
7
8
Percent of BC Patients* With Notable Serum
Creatinine Increase Was Similar in the Zoledronic
Acid and Pamidronate Groups
50
Zol 4 mg
Pam 90 mg
Patients, %
40
30
20
10
9.4
6.5
0
n = 181
n = 184
*Safety-evaluable patients treated post–15-minute infusion amendment.
Lipton A, et al. Presented at: 4th European Breast Cancer Conference. 2004:
Poster 296.
No NCI Grade 3 or 4 Serum Creatinine Increases
Occurred in Breast Cancer Patients Treated With
Zoledronic Acid*
Patients, n (%)
Zol 4 mg
n = 181
Pam
n = 184
Grade 3 (> 3.0 - 6.0  ULN)
0
0
Grade 4 (> 6.0  ULN)
0
1 (0.5)
NCI = National Cancer Institute; ULN = Upper limit of normal (1.2 mg/dL).
*Safety-evaluable patients treated post–15-minute infusion amendment.
Lipton A, et al. Presented at: 4th European Breast Cancer Conference. 2004:
Poster 296.
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Conclusions
 Zoledronic acid (4 mg via 15-minute infusion) has a
renal safety profile comparable to that of pamidronate
(90 mg via 2-hour infusion) in patients with breast
cancer
 There was a low incidence of NCI Common Toxicity
Criteria grade 3 or 4 serum creatinine increase
–
No patient with breast cancer treated with 4 mg
zoledronic acid via 15-minute infusion experienced
grade 3 or 4 serum creatinine elevation
NCI = National Cancer Institute.
Lipton A, et al. Presented at: 4th European Breast Cancer Conference.
2004: Poster 296.
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Serum Creatinine After 3 Months of IV
Bisphosphonate Therapy in Patients With BC
Ibandronate
(6 mg over 1 hr)
Placebo
Zoledronic acid*
(4 mg over 15 min)
Pamidronate
(90 mg over 2 hrs)
n
28
Mean serum creatinine  SD, mmol/L
Baseline
Month 3
80.9  2.0
84.8  2.2
23
83.4  3.9
89.1  3.0
181
81.4  13.6
78.9  15.0
184
81.9  17.2
80.8  16.4
*Within the first 3 months of treatment, no patient treated with zoledronic acid
(4 mg over 15 minutes) experienced a notable serum creatinine increase
(based on defined criteria).
Lipton A, et al. Presented at: 4th European Breast Cancer Conference.
2004: Poster 296.
Lyubimova NV, et al. Clin Drug Invest, 2003; 23: 707-716.
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TGA approved indications:
 Prevention of skeletal-related events (pathological
fracture, spinal cord compression, radiation to bone
or surgery to bone) in patients with advanced
malignancies involving bone.
 Treatment of tumour-induced hypercalcaemia.
Please review full Product Information before prescribing.
For further information please contact Novartis, 1800 814 667.
ABN 18 004211 160. 54 Waterloo Road North Ryde NSW 2113.
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PBS LISTING:
•
Bone metastases from hormone-resistant prostate cancer, with
demonstration of biochemical progression of disease despite maximal
therapy with hormonal treatments;
•
Multiple Myeloma
•
Bone metastases from Breast Cancer
•
Treatment of hypercalcaemia of malignancy refractory to anti-neoplastic
therapy
PBS Information: Zometa is listed on the PBS (Section 100) for the treatment of patients with
multiple myeloma, bone metastases from breast cancer and bone metastases from hormoneresistant prostate cancer. Refer to PBS schedule for full information.
Please review full Product Information before prescribing.
For further information please contact Novartis, 1800 814 667.
ABN 18 004211 160. 54 Waterloo Road North Ryde NSW 2113.