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Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease
Annals of Oncology 10: 311-316, 1999. © 1999 Khmer Academic Publishers. Primed in the Netherlands
Original article Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease R. E. Coleman,1 O. P. Purohit,1 C. Black,1 J. J. F.Vinholes,1 K. Schlosser,2 H. Huss,2 K. J. Quinn2 & J. Kanis3 ' Yorkshire Cancer Research Department of Clinical Oncology. Weston Park Hospital, Sheffield, UK; ~Boehringer Mannheim Therapeutics, Livingstone, Scotland and Mannheim, Germany; 3Department of Human Metabolism & Clinical Biochemistry, Royal Hallamshire Hospital, Sheffield, UK
Summary
were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% 80% and 74% respectively. One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5,10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concommitant administration of non-steroidal antiinflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across thefivetreatment groups. There was no difference in non-GI adverse events between groups. Conclusions: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.
Background: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed. Patients and methods: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebocontrolled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a futher three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. Results: Two patients did not receive any trial medication Key words: bone resorption markers, ibandronate, metastatic thus, 108 patients were evaluable for safety. Ninety-two patients bone disease
Introduction The bisphosphonates are an important new class of agents for the treatment of metastatic bone disease. In addition to their confirmed status as the treatment of choice for hypercalcaemia of maligancy [1-3], randomised controlled trials have clearly demonstrated that long-term bisphosphonate treatment is effective in reducing skeletal morbidity in breast cancer [4-6] and multiple myeloma [7-9] with fewer skeletal related events, reduced pain and analgesic consumption, and improved quality of life. Both regular monthly infusions of pamidronate [4, 5, 9] and daily oral administration of clodronate [6-8] have been shown to be of clinical value; however repeated intravenous infusions are inconvenient for patients, while the efficacy of the currently available oral bisphospho-
nates is compromised by poor absorption (0.5%-4%) from the gastrointestinal (GI) tract and in some instances by GI toxicity, particularly dyspepsia including occasional oesophagitis, nausea and vomiting, abdominal pain and diarrhoea [10,11]. Ibandronate is a highly potent amino-bisphosphonate which is licensed in Europe for the treatment of hypercalcaemia of malignancy, and in clinical development for both the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. Bisphosphonates are known to show dose-dependent inhibition of retinoid-induced hypercalcaemia in the thyroparathyroidectomized rat, and in this model ibandronate was found to be about 2, 10, 50 and 500 times more potent than risedronate, alendronate, pamidronate and clodronate respectively [12]. The intravenous route was 100 times more effective than oral administration, re-
312 fleeting the typical poor absorption of bisphosphonates. However with such a potent agent, it is anticipated that sufficient amounts of oral ibandronate would be absorbed to inhibit effectively the accelerated bone resorption associated with metastatic bone disease. Originally an oral capsule was developed but this resulted in an unacceptably high incidence of gastro-intestinal adverse events [13]. As a result new formulations were developed including a film-coated tablet which, in animal models, exhibited the same effects on bone resorption as the original capsule. The primary aim of this study was to define an effective oral dose of the film-coated ibandronate tablet for the treatment of metastatic bone disease. The safety profile and effects of different doses of ibandronate on the urinary excretion of urinary calcium and specific markers of bone resorption were evaluated over a 28-day treatment period.
Table 1. Patient characteristics (n = 110). Sex Female Male Disease Breast Prostate Kidney Lung Myeloma Others Age 20-39 40-59 60-79 >80 Baseline UCCR (median values) Placebo 5 mg 10 mg 20 mg 50 mg
84 26 77 16 4 3 3 7 6 59 43 2 0.33 0.26 0.43 0.37 0.43
Patients and methods One hundred ten patients with radiologically confirmed bone metastases (77 breast, 16, prostate, 17 others) with a median age of 57 years (range 20-86) were recruited over a 12 month period from a single institution to a double blind placebo-controlled evaluation of the bisphosphonate, ibandronate (BM 21.0955). Patients were randomly allocated to placebo or 1 of 4 oral dose levels (5,10, 20 and 50 mg) given daily. The characteristics of the study population are shown in Table 1. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. At least two weeks had to have elapsed since radiotherapy to bone metastases. Patients with abnormal serum calcium (albumin corrected level either >2.7 mmol/1 or <2.0 mmol/1), a history of primary hyperparathyroidism, Paget's disease of bone, or receiving other drugs known to affect bone metabolism were ineligible. The study was approved by the South Sheffield Research Ethics Committee and all patients gave written informed consent prior to study entry. Patients were instructed to take the ibandronate (placebo) tablet in the morning one hour before breakfast or the consumption of drinks containing dairy products. Patients were advised not to return to bed after taking ibandronate to minimise lodging of the medication in the oesophagus. After an initial four week tolerability and efficacy phase, patients were invited to continue on treatment, without unblinding the study, for a further three months with the aim of collecting additional safety data. Patients continued on the same dose of ibandronate with the exception of those patients who had been allocated to the placebo group during the first month; these patients received 50 mg ibandronate daily. On completion of the entire four month study period, patients experiencing subjective benefit could continue oral ibandronate on a named-patient basis. Calcium supplements were not prescribed. Biochemical assessment of bone resorption was measured twice before commencing treatment and at weekly intervals during the fourweek placebo controlled phase of the study. Patients were advised to collect the second morning urine following an overnight fast and serum was collected as early in the morning as possible for measurement of bone formation markers, routine haematology and biochemistry, and drug levels. As in previous studies [14, 15]. all urine samples were acidified to prevent precipitation of insoluble calcium-phosphate complexes by the addition of I ml IN (3%) hydrochloric acid for every 20 ml urine and stored frozen at -20 C until analysis. The primary variable was urinary calcium excretion calculated as a ratio of urinary calcium to urinary creatinine (UCCR). Bone resorption was also assessed by measurement of collagen crosslink excretion in the urine. Total pyridinoline (Pyr) and deoxypyridinoline (Dpd) excretion were measured by reversed-phase high performance liquid
chromatography (HPLC) [16]. In a previous study, the upper limit of normal for Pyr and Dpd were 41.7 and 11.8 nmol/mmol creatinine respectively [14]. The peptide bound N-terminal and C-terminal portions of the collagen crosslinking molecules were measured by an enzyme-linked immunoabsorbent assay (ELISA) using the Osteomark® (NTX, Ostex®) [17] and Crosslaps® (CTX, Osteometer®) [18] assays respectively. With these assays, the upper limit of normal for NTX is 65 and 131 nMBCE/mM creatinine and for Crosslaps is 50 and 80 ug/mmol creatinine in premenopausal women/men and postmenopausal women respectively. Bone formation was assessed by serum measurements of osteocalcin using an ELISA assay to the mid molecular epitope (Osteometer1"1) [19], the bone specific isoenzyme of alkaline phosphatase (Boehringer Mannheim*), and the C-terminal propeptide of type 1 procollagen (PICP) (Osteometer A/S*) [20], Tolerability was assessed weekly by the same study nurse throughout the trial and all adverse events (AE) graded as mild (no interuption/ change in study drug necessary), moderate (study drug interupted or discontinued) or severe (life-threatening or requiring hospitalisation). Compliance was assessed by tablet counts at each visit and measurement of serum levels of ibandronate using an ELISA assay developed by Boehringer Mannheim. The lower limit of detection was 50 pg/ml. Although not a primary aim of the study, an attempt to assess the effect of treatment on bone pain and analgesic consumption was made at each clinic visit during the first four-week placebo-controlled phase using the pain and anlagesic scoring system described previously by Coleman et al. [21]. An ANalysis of COVAriance was used for analysis of the primary variable (UCCR) and the other bone resorption and formation markers. The relative change between groups was compared using the Kruskal Wallis test and pairwise comparisons of each two treatment groups made by the Wilcoxon rank-sum test. In addition the time normed Area Under the Curve (AUC) was calculated using the trapezoid formula for additional analyses of the changes in bone resorption markers.
Results
The treatment groups were well balanced for age, height, weight, disease type and baseline urinary calcium and collagen crosslink excretion. Two patients did not receive any trial medication due to hypercalcaemia. This
313 (a)
Table 2. Efficacy results.
0.500.45"
Urinary excretion of resorption markers expressed as the percentage at day 28 of the baseline value - median values Calcium (mmol/ mmol)
Pyr
(umol/ mmol)
Dpd
(umol/ mmol)
Crosslaps (mg/ mmol)
(nmol BCE/ mmol)
97 48 45 32 20
100 47 60 42 26
Ntx
0.40"o
0J5-
|
030"
B
O25"
a u
O200.150.10"
Placebo (n = 15) 5mg(n-18) 10mg(n=21) 20mg(n = 18) 50 mg (;i = 20)
120 87 42 33 29
102 95 92 90 72
106 96 77 73 61
0.05"
weeks
(b)
Urinary excretion of resorption markers; time normed percentage area under the curve (AUC) in relation to baseline - median values
Placebo 5mg
10 mg 20 mg 50 mg
Calcium (mmol/ mmol)
Pyr
Dpd
(Umol/ mmol)
Crosslaps (mg/ mmol)
Ntx
(umol/ mmol)
122 88 64 47 45
102 99 92 91 83
103 95 84 85 75
105 86 77 55 34
128 99 82 63 54
(nmol BCE/ mmol)
Bone formation markers expressed as the percentage relative change from baseline at day 28 - median values
Placebo 5 mg 10 mg 20 mg 50 mg
ALP-BI (U/l)
Osteocalcin (ng/ml)
PICP (ng/ml)
106 103 98 126 77
101 97 97 87 95
108
96 94 94 90
was during the screening phase in one and due to withdrawal of consent in the other; thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy with sixteen patients excluded from the per protocol analysis because of early study withdrawal due to AE (ten patients), radiotherapy to bone lesions (two patients), high-dose corticosteroids administered (one patient), early death (one patient), lost to follow-up (one patient), poor compliance (one patient). Table 2 shows the effects of the four different doses of ibandronate and placebo tablets on bone metabolism. A dose dependent reduction in the biochemical markers of bone resorption was observed with the greatest changes seen in urinary calcium excretion and the peptide-bound fragments of type 1 collagen - Ntx and Crosslaps. Similar results were seen in all tumour types. There was no significant effect of treatment at any dose level on the three markers of bone formation. Figure 1 illustrates the time course of changes in urinary calcium for the five groups. The maximum
4
weeks
Figure 1. Time course of median (top) and percentage change from baseline (bottom) in urinary calcium creatinine ratio (UCCR) for the four dosage levels of ibandronate and placebo.
suppression of urinary calcium was achieved by day 7 with ibandronate 20 mg and 50 mg, and by day 21 with ibandronate 10 mg; the 5 mg dose was less effective at all time points. The data show that there is a difference between placebo, 5 mg and 10 mg and between these three groups and 20 mg and 50 mg. ANalysis of COVAriance comparing the four-week value of UCCR between treatment groups with the baseline values indicated a significant overall effect of dose (P < 0.001) and also a statistically significant contribution of the baseline value of UCCR (P < 0.001, Table 3). The baseline median values of the collagen crosslink measurements were in the region of that seen in early post-menopausal women indicating accelerated bone resorption. In Figure 2 the changes observed in urinary deoxypyridinoline (Dpd) excretion illustrate the dosedependent effects on bone resorption more clearly. Again the ANalysis of COVariance showed a dose-response relationship (P < 0.0023) and a statistically significant contribution of the baseline value (P < 0.0001, Table 3). All doses of ibandronate brought the mean urinary Crosslaps and Ntx excretion for each treatment group into the normal range (i.e., below the mean value of premenopausal women). A dose-response relationship (Crosslaps P < 0.0004; Ntx P < 0.007) and a statistically significant contribution of the baseline values (Crosslaps and Ntx P < 0.0001) were seen. The AUC analyses confirmed the findings comparing four-week values with baseline and are shown in Table 3 for all the bone resorption markers.
314 Table 3. Comparison of placebo to active dose groups and exploratory analysis between dose groups at four weeks using an ANalysis of CO Variance Model for urinary calcium/creatinine ratio (UCCR), Dpd and Crosslaps.
UCCR (mmol/mmol)
Dpd (umol/mol)
Crosslaps (mg/mmol)
Group
Placebo
5 mg
10 mg
20 mg
5 mg 10 mg 20 mg 50 mg
0.0007 0.0001 0.0001 0.0001
0.0301 0.0032 0.0001
0.3177 0.0313
0.2795
5 mg lOmg 20 mg 50 mg
0.6264 0.4628 0.0924 0.0005
5mg 10 mg 20 mg 50 mg
0.005 0.1697 0.0044 0.0001
0.8110
-
0.2049 0.0017
0.2832 0.0019
0.1066 0.9656 0.1712
0.0964 0.0019
0.0635
0.1831
110 n
Table 4. Serum values of ibandronate (pg/ml).
Median Mean Range
5mg
10 mg
20 mg
50 mg
0 717 0-5832
815 1186 0-4838
2166 3060 0-6697
5502 9935 1890-65396
Table 5. Safety results: Gastrointestinal adverse events (AE) during the placebo controlled (weeks 0-4) and follow-on (weeks 5-16) phases of the study. Adverse events
Weeks 0-4 Nausea/ vomiting Dyspepsia/ indigestion/ abdominal pain Bowel dysfunction Diarhoea Total number of patients with one or more A E
Adverse events
Placebo
- » "
4
50mg(i»21)
weeks
Figure 2. Percentage change from baseline in median values of urinary deoxypyridinoline (Dpd) excretion for the four dosage levels of ibandronate and placebo.
Weeks 5-16 Nausea/vomiting Dyspepsia/ indigestion/ abdominal pain Diarrhoea Constipation Total number of patients with one or more AE
Placebo (« = 20)
5 mg
10 mg (« = 23)
20 mg 50 mg (« = 22) (« = 22)
6 (30%)
7 (33%)
9 (39%)
9 (41%)
5 mg (« = I7)
lOmg (n = 22)
20mg 50mg (n = 17) (« = 35)
II (50%)
1
2
4
4
4 0 0
4 4 1
5 2 4
9 4 1
5 (29%)
10 (45%)
10 (59%)
15 (43%)
Expressed in patient years, the total treatment duration for the 108 patients was 31.3 years. The exposure to 50 mg was double that of the other groups at 8.05 years in comparison to the number experienced at the 10 mg, because patients on placebo converted to ibandronate 20 mg and 50 mg dose levels (13 of 41 [32%] vs. 29 of 50 mg after the first four weeks. Compliance appeared 67 [43%]). In the three-month follow-on study all doses to be good and the serum levels obtained in 65 patients showed similar tolerability (Table 5); patients who on day 21 of ibandronate reflected the administered dose switched from placebo to 50 mg had the same incidence (Table 4). The ibandronate serum level was below the of GI adverse events as those who started on 50 mg. lower limit of detection in 15 (23%) of patients (seven at Nine (8%) patients stopped treatment within the first 5 mg, seven at 10 mg and one at 20 mg). month due to GI intolerability but these patients were In general, ibandronate was well tolerated. One or evenly distributed across the five treatment groups. GI more gastrointestinal (GI) adverse events occuring in tolerability may have been adversely affected by conthe first month of treatment were reported by six (30%), commitant administration of non-steroidal anti-inflamseven (33%), nine (39%), nine (41%) and eleven (50%) matory agents although the study numbers were too patients at the placebo, 5, 10, 20 and 50 mg dose levels small to confirm this clinical impression. There was no respectively (Table 5). One patient on ibandronate 20 mg difference in non-GI adverse events between groups. developed severe dysphagia with oesophageal ulceration Although individual patients reported improvements clearly demonstrated on barium swallow examination in bone pain and were able to reduce their analgesic approximately one week after starting treatment. intake, no significant effects of treatment over time or The incidence of GI adverse events in the 5 mg treat- between the treatment groups were demonstrated. ment group was comparable to that experienced by the Twenty-three patients who reported clinical benefit and placebo group, and slightly less (but not significantly so) good tolerability at the end of the four-month study
315 period requested continued treatment with oral ibandronate in the context of named patient supplies for 3-36+ months. These requests were evenly spread across the treatment groups. Discussion On the basis of changes in biochemical markers of the rate of bone resorption, this study of oral ibandronate has clearly demonstrated efficacy at doses which were generally well tolerated. A four-week treatment reduced the excretion of calcium and collagen crosslinks in the urine with a clear dose response relationship; 5 mg was the minimum effective dose and the largest changes were seen at the 20 mg and 50 mg dose levels. The reduction in urinary calcium excretion was the primary endpoint of the study since this was the most widely used indicator of bisphosphonate effects on calcium metabolism at the time the study was initiated. The fasting urinary excretion of calcium integrates both resorption and formation and it thus provides a marker of net resorption. Recent studies have shown that urinary calcium correlates poorly with the collagen crosslink measurements of bone resorption due to the influence of acute changes in parathyroid hormone induced by bisphosphonates [14, 15, 24]. In recent years more sensitive and specific markers of bone resorption have been developed which we used as secondary end-points [14, 15, 22]. The excretion of the collagen breakdown products pyridinoline and deoxypyridinoline and the protein bound fragments identified by the Ntx and CTX assays confirmed a clear doseresponse relationship with, as seen in previous bisphosphonate studies [22, 23], the greatest changes occuring in the urinary levels of the protein bound crosslinks. An ANalysis of COVAriance model showed that for most comparisons the 20 mg and 50 mg doses were more effective than the 5 mg and 10 mg doses. A much larger study would be necessary to define the optimum dose with more precision. As we have observed in previous studies, there were no significant differences in the biochemical responses observed in the breast cancer patients compared with the other tumour types (data not shown) [24, 25]. As expected there were occasional patients who could not tolerate oral ibandronate due to gastrointestinal adverse events. A slight excess of GI adverse events occured at the 10 mg, 20 mg and 50 mg dosages but the number of patients who discontinued treatment because of adverse events was similar in all groups including placebo. GI adverse events were usually reported in the first 14 days of treatment such that the identification of patients unable to tolerate oral ibandronate was relatively straightforward. Apart from the one patient with oesophageal ulceration, all GI adverse events resolved on discontinuation of therapy within 24-48 hours. The subjective benefits of oral ibandronate were difficult to demonstrate in this study, despite a relatively
large cohort of patients receiving treatment unconfounded by other anticancer treatments. Undoubtedly individual patients reported significant and occasionally long-lasting improvement in pain but no consistent effect could be demonstrated. Reports of pain relief were unrelated to the dose of ibandronate or the changes observed in bone resorption markers. This is in contrast to the very clear effects of intravenous pamidronate [24], clodronate [26] and zoledronate [27] in reducing bone pain and analgesic consumption, and improving mobility and quality of life through effective reversal of the tumour induced increase in bone resorption rates [24, 28]. Interestingly, although a reduction in skeletal related events has been demonstrated with oral bisphosphonates [6-8], acute pain relief in metastatic bone disease has also not been convincingly demonstrated with either oral clodronate [29] or pamidronate [10]. For acute relief of severe bone pain, high doses of intravenous bisphosphonate appear to be necessary. In conclusion ibandronate is a generally well tolerated oral amino-bisphosphonate with rapid and clear effects on surrogate markers of bone resorption. The 20 mg and 50 mg tablets would appear to be the most promising doses to take forward into phase III development in metastatic bone disease.
References 1. Body JJ, Borkowski A, Cleeren A, Bijvoet OLM. Treatment of malignancy-associated hypercalcemia with intravenous aminohydroxypropylidene diphosphonate (APD). J Clin Oncol 1986; 4: 1177-83. 2. O'Rourke NP. McCloskey EV, Vasikaran S et al. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br J Cancer 1993; 67: 560-3. 3. Purohit OP, Radstone CR, Anthony C et al. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995; 72: 1289-93. 4. Hortobagyi GN, Theriault RL, Porter L et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996; 335: 1785-91. 5. Lipton A, Theriault R, Leff R et al. Long-term reduction of skelelal complications in breast cancer patients with osteolytic bone metastases receiving hormone therapy, by monthly 90 mg pamidronate (Aredia®) infusions. Proc ASCO 1997; 16: 152a. 6. Patterson AHG, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59-65. 7. Lahtinen R, Laakso M, Palva I et al. for the Finnish Leukaemia Group. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992; 340: 1049-52. 8. McCloskey EV, Maclennan ICM, Drayson M et al. A randomised trial of the effect of clodronate on skeletal morbidity in multiple myeloma. Br J Haematol 1998; 100: 317-25. 9. Berenson JR, Lichtenstein A, Porter L et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 1996; 334: 488-93. 10. Coleman RE, Houston S, Purohit OP et al. A randomised phase II evaluation of oral pamidronate for advanced bone metastases from breast cancer. Eur J Cancer 1998; 34: 820-4. 11. De Groen PC, Lubbe DF, Hirsch LJ et al. Oesophagitis associated with the use of alendronate. N Engl J Med 1996; 335: 1016-21.
316 12. Muhlbauer RC, Bauss F, Schenk R et al. BM21.0955, a potent new bisphosphonate to inhibit bone resorption. J Bone Miner Res 1991:6: 1003-11. 13. Bauss F, Muhlbauer RC. Ibandronate, monosodium salt, monohydrate. Drugs Future 1994; 19: 13-6. 14. Vinholes JJ. Guo C-Y, Purohit OP et al. Metabolic effects of pamidronate in patients with metastatic bone disease. Br J Cancer 1996; 73: 1089-95. 15. Vinholes J, Guo C-Y, Purohit OP et al. Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcaemia of malignancy. J Chn Oncol 1997; 15: 131-8. 16. Siebel MJ, Robins SP, Bilezikian JP. Urinary pyridinium crosslinks of collagen. Specific marker of bone resorption in metabolic bone disease. Trends Endocnnol Metab 1992; 3; 263-70. 17. Hanson D, Weis MAE, Bollen AM et al. A specific immunoassay for monitoring human bone resoption: Quantification of type I collagen cross-linked N-telopeptides in urine. J Bone Miner Res 1992; 7: 1251-8. 18. Bonde M, Qvist P, Chriastensen C et al. Applications of an enzyme immunoassay for a new marker of bone resorption (Crosslaps): Follow-up on hormone replacement therapy and osteoporosis risk assessment. J Clin Endocrinol Metab 1995; 80: 864-8. 19. Rosenquist C, Bonde M, Fledulus C, Qvist P. A simple enzymelinked immuno-adsorbent assay of human osteocalcin. Clin Chem 1994; 40: 1258-64. 20. Melkko J, Niemi S, Risteli J. Radioimmunoassay of the carboxyterminal propeptide of human type 1 procollagen. Clin Chem 1990; 36: 1328-32. 21. Coleman RE, Whitaker KD, Moss DW et al. Biochemical monitoring predicts response in bone to systemic treatment. Br J Cancer 1988; 58: 205-10. 22. Vinholes J, Coleman R, Eastell R. Effects of bone metastases on bone metabolism: Implications for diagnosis, imaging and assess-
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Received 1 October 1998; accepted 13 January 1999.
Correspondence lo: Dr R. E. Coleman YCR Department of Clinical Oncology Weston Park Hospital Sheffield S10 2SJ UK
Original article Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease R. E. Coleman,1 O. P. Purohit,1 C. Black,1 J. J. F.Vinholes,1 K. Schlosser,2 H. Huss,2 K. J. Quinn2 & J. Kanis3 ' Yorkshire Cancer Research Department of Clinical Oncology. Weston Park Hospital, Sheffield, UK; ~Boehringer Mannheim Therapeutics, Livingstone, Scotland and Mannheim, Germany; 3Department of Human Metabolism & Clinical Biochemistry, Royal Hallamshire Hospital, Sheffield, UK
Summary
were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% 80% and 74% respectively. One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5,10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concommitant administration of non-steroidal antiinflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across thefivetreatment groups. There was no difference in non-GI adverse events between groups. Conclusions: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.
Background: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed. Patients and methods: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebocontrolled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a futher three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. Results: Two patients did not receive any trial medication Key words: bone resorption markers, ibandronate, metastatic thus, 108 patients were evaluable for safety. Ninety-two patients bone disease
Introduction The bisphosphonates are an important new class of agents for the treatment of metastatic bone disease. In addition to their confirmed status as the treatment of choice for hypercalcaemia of maligancy [1-3], randomised controlled trials have clearly demonstrated that long-term bisphosphonate treatment is effective in reducing skeletal morbidity in breast cancer [4-6] and multiple myeloma [7-9] with fewer skeletal related events, reduced pain and analgesic consumption, and improved quality of life. Both regular monthly infusions of pamidronate [4, 5, 9] and daily oral administration of clodronate [6-8] have been shown to be of clinical value; however repeated intravenous infusions are inconvenient for patients, while the efficacy of the currently available oral bisphospho-
nates is compromised by poor absorption (0.5%-4%) from the gastrointestinal (GI) tract and in some instances by GI toxicity, particularly dyspepsia including occasional oesophagitis, nausea and vomiting, abdominal pain and diarrhoea [10,11]. Ibandronate is a highly potent amino-bisphosphonate which is licensed in Europe for the treatment of hypercalcaemia of malignancy, and in clinical development for both the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. Bisphosphonates are known to show dose-dependent inhibition of retinoid-induced hypercalcaemia in the thyroparathyroidectomized rat, and in this model ibandronate was found to be about 2, 10, 50 and 500 times more potent than risedronate, alendronate, pamidronate and clodronate respectively [12]. The intravenous route was 100 times more effective than oral administration, re-
312 fleeting the typical poor absorption of bisphosphonates. However with such a potent agent, it is anticipated that sufficient amounts of oral ibandronate would be absorbed to inhibit effectively the accelerated bone resorption associated with metastatic bone disease. Originally an oral capsule was developed but this resulted in an unacceptably high incidence of gastro-intestinal adverse events [13]. As a result new formulations were developed including a film-coated tablet which, in animal models, exhibited the same effects on bone resorption as the original capsule. The primary aim of this study was to define an effective oral dose of the film-coated ibandronate tablet for the treatment of metastatic bone disease. The safety profile and effects of different doses of ibandronate on the urinary excretion of urinary calcium and specific markers of bone resorption were evaluated over a 28-day treatment period.
Table 1. Patient characteristics (n = 110). Sex Female Male Disease Breast Prostate Kidney Lung Myeloma Others Age 20-39 40-59 60-79 >80 Baseline UCCR (median values) Placebo 5 mg 10 mg 20 mg 50 mg
84 26 77 16 4 3 3 7 6 59 43 2 0.33 0.26 0.43 0.37 0.43
Patients and methods One hundred ten patients with radiologically confirmed bone metastases (77 breast, 16, prostate, 17 others) with a median age of 57 years (range 20-86) were recruited over a 12 month period from a single institution to a double blind placebo-controlled evaluation of the bisphosphonate, ibandronate (BM 21.0955). Patients were randomly allocated to placebo or 1 of 4 oral dose levels (5,10, 20 and 50 mg) given daily. The characteristics of the study population are shown in Table 1. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. At least two weeks had to have elapsed since radiotherapy to bone metastases. Patients with abnormal serum calcium (albumin corrected level either >2.7 mmol/1 or <2.0 mmol/1), a history of primary hyperparathyroidism, Paget's disease of bone, or receiving other drugs known to affect bone metabolism were ineligible. The study was approved by the South Sheffield Research Ethics Committee and all patients gave written informed consent prior to study entry. Patients were instructed to take the ibandronate (placebo) tablet in the morning one hour before breakfast or the consumption of drinks containing dairy products. Patients were advised not to return to bed after taking ibandronate to minimise lodging of the medication in the oesophagus. After an initial four week tolerability and efficacy phase, patients were invited to continue on treatment, without unblinding the study, for a further three months with the aim of collecting additional safety data. Patients continued on the same dose of ibandronate with the exception of those patients who had been allocated to the placebo group during the first month; these patients received 50 mg ibandronate daily. On completion of the entire four month study period, patients experiencing subjective benefit could continue oral ibandronate on a named-patient basis. Calcium supplements were not prescribed. Biochemical assessment of bone resorption was measured twice before commencing treatment and at weekly intervals during the fourweek placebo controlled phase of the study. Patients were advised to collect the second morning urine following an overnight fast and serum was collected as early in the morning as possible for measurement of bone formation markers, routine haematology and biochemistry, and drug levels. As in previous studies [14, 15]. all urine samples were acidified to prevent precipitation of insoluble calcium-phosphate complexes by the addition of I ml IN (3%) hydrochloric acid for every 20 ml urine and stored frozen at -20 C until analysis. The primary variable was urinary calcium excretion calculated as a ratio of urinary calcium to urinary creatinine (UCCR). Bone resorption was also assessed by measurement of collagen crosslink excretion in the urine. Total pyridinoline (Pyr) and deoxypyridinoline (Dpd) excretion were measured by reversed-phase high performance liquid
chromatography (HPLC) [16]. In a previous study, the upper limit of normal for Pyr and Dpd were 41.7 and 11.8 nmol/mmol creatinine respectively [14]. The peptide bound N-terminal and C-terminal portions of the collagen crosslinking molecules were measured by an enzyme-linked immunoabsorbent assay (ELISA) using the Osteomark® (NTX, Ostex®) [17] and Crosslaps® (CTX, Osteometer®) [18] assays respectively. With these assays, the upper limit of normal for NTX is 65 and 131 nMBCE/mM creatinine and for Crosslaps is 50 and 80 ug/mmol creatinine in premenopausal women/men and postmenopausal women respectively. Bone formation was assessed by serum measurements of osteocalcin using an ELISA assay to the mid molecular epitope (Osteometer1"1) [19], the bone specific isoenzyme of alkaline phosphatase (Boehringer Mannheim*), and the C-terminal propeptide of type 1 procollagen (PICP) (Osteometer A/S*) [20], Tolerability was assessed weekly by the same study nurse throughout the trial and all adverse events (AE) graded as mild (no interuption/ change in study drug necessary), moderate (study drug interupted or discontinued) or severe (life-threatening or requiring hospitalisation). Compliance was assessed by tablet counts at each visit and measurement of serum levels of ibandronate using an ELISA assay developed by Boehringer Mannheim. The lower limit of detection was 50 pg/ml. Although not a primary aim of the study, an attempt to assess the effect of treatment on bone pain and analgesic consumption was made at each clinic visit during the first four-week placebo-controlled phase using the pain and anlagesic scoring system described previously by Coleman et al. [21]. An ANalysis of COVAriance was used for analysis of the primary variable (UCCR) and the other bone resorption and formation markers. The relative change between groups was compared using the Kruskal Wallis test and pairwise comparisons of each two treatment groups made by the Wilcoxon rank-sum test. In addition the time normed Area Under the Curve (AUC) was calculated using the trapezoid formula for additional analyses of the changes in bone resorption markers.
Results
The treatment groups were well balanced for age, height, weight, disease type and baseline urinary calcium and collagen crosslink excretion. Two patients did not receive any trial medication due to hypercalcaemia. This
313 (a)
Table 2. Efficacy results.
0.500.45"
Urinary excretion of resorption markers expressed as the percentage at day 28 of the baseline value - median values Calcium (mmol/ mmol)
Pyr
(umol/ mmol)
Dpd
(umol/ mmol)
Crosslaps (mg/ mmol)
(nmol BCE/ mmol)
97 48 45 32 20
100 47 60 42 26
Ntx
0.40"o
0J5-
|
030"
B
O25"
a u
O200.150.10"
Placebo (n = 15) 5mg(n-18) 10mg(n=21) 20mg(n = 18) 50 mg (;i = 20)
120 87 42 33 29
102 95 92 90 72
106 96 77 73 61
0.05"
weeks
(b)
Urinary excretion of resorption markers; time normed percentage area under the curve (AUC) in relation to baseline - median values
Placebo 5mg
10 mg 20 mg 50 mg
Calcium (mmol/ mmol)
Pyr
Dpd
(Umol/ mmol)
Crosslaps (mg/ mmol)
Ntx
(umol/ mmol)
122 88 64 47 45
102 99 92 91 83
103 95 84 85 75
105 86 77 55 34
128 99 82 63 54
(nmol BCE/ mmol)
Bone formation markers expressed as the percentage relative change from baseline at day 28 - median values
Placebo 5 mg 10 mg 20 mg 50 mg
ALP-BI (U/l)
Osteocalcin (ng/ml)
PICP (ng/ml)
106 103 98 126 77
101 97 97 87 95
108
96 94 94 90
was during the screening phase in one and due to withdrawal of consent in the other; thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy with sixteen patients excluded from the per protocol analysis because of early study withdrawal due to AE (ten patients), radiotherapy to bone lesions (two patients), high-dose corticosteroids administered (one patient), early death (one patient), lost to follow-up (one patient), poor compliance (one patient). Table 2 shows the effects of the four different doses of ibandronate and placebo tablets on bone metabolism. A dose dependent reduction in the biochemical markers of bone resorption was observed with the greatest changes seen in urinary calcium excretion and the peptide-bound fragments of type 1 collagen - Ntx and Crosslaps. Similar results were seen in all tumour types. There was no significant effect of treatment at any dose level on the three markers of bone formation. Figure 1 illustrates the time course of changes in urinary calcium for the five groups. The maximum
4
weeks
Figure 1. Time course of median (top) and percentage change from baseline (bottom) in urinary calcium creatinine ratio (UCCR) for the four dosage levels of ibandronate and placebo.
suppression of urinary calcium was achieved by day 7 with ibandronate 20 mg and 50 mg, and by day 21 with ibandronate 10 mg; the 5 mg dose was less effective at all time points. The data show that there is a difference between placebo, 5 mg and 10 mg and between these three groups and 20 mg and 50 mg. ANalysis of COVAriance comparing the four-week value of UCCR between treatment groups with the baseline values indicated a significant overall effect of dose (P < 0.001) and also a statistically significant contribution of the baseline value of UCCR (P < 0.001, Table 3). The baseline median values of the collagen crosslink measurements were in the region of that seen in early post-menopausal women indicating accelerated bone resorption. In Figure 2 the changes observed in urinary deoxypyridinoline (Dpd) excretion illustrate the dosedependent effects on bone resorption more clearly. Again the ANalysis of COVariance showed a dose-response relationship (P < 0.0023) and a statistically significant contribution of the baseline value (P < 0.0001, Table 3). All doses of ibandronate brought the mean urinary Crosslaps and Ntx excretion for each treatment group into the normal range (i.e., below the mean value of premenopausal women). A dose-response relationship (Crosslaps P < 0.0004; Ntx P < 0.007) and a statistically significant contribution of the baseline values (Crosslaps and Ntx P < 0.0001) were seen. The AUC analyses confirmed the findings comparing four-week values with baseline and are shown in Table 3 for all the bone resorption markers.
314 Table 3. Comparison of placebo to active dose groups and exploratory analysis between dose groups at four weeks using an ANalysis of CO Variance Model for urinary calcium/creatinine ratio (UCCR), Dpd and Crosslaps.
UCCR (mmol/mmol)
Dpd (umol/mol)
Crosslaps (mg/mmol)
Group
Placebo
5 mg
10 mg
20 mg
5 mg 10 mg 20 mg 50 mg
0.0007 0.0001 0.0001 0.0001
0.0301 0.0032 0.0001
0.3177 0.0313
0.2795
5 mg lOmg 20 mg 50 mg
0.6264 0.4628 0.0924 0.0005
5mg 10 mg 20 mg 50 mg
0.005 0.1697 0.0044 0.0001
0.8110
-
0.2049 0.0017
0.2832 0.0019
0.1066 0.9656 0.1712
0.0964 0.0019
0.0635
0.1831
110 n
Table 4. Serum values of ibandronate (pg/ml).
Median Mean Range
5mg
10 mg
20 mg
50 mg
0 717 0-5832
815 1186 0-4838
2166 3060 0-6697
5502 9935 1890-65396
Table 5. Safety results: Gastrointestinal adverse events (AE) during the placebo controlled (weeks 0-4) and follow-on (weeks 5-16) phases of the study. Adverse events
Weeks 0-4 Nausea/ vomiting Dyspepsia/ indigestion/ abdominal pain Bowel dysfunction Diarhoea Total number of patients with one or more A E
Adverse events
Placebo
- » "
4
50mg(i»21)
weeks
Figure 2. Percentage change from baseline in median values of urinary deoxypyridinoline (Dpd) excretion for the four dosage levels of ibandronate and placebo.
Weeks 5-16 Nausea/vomiting Dyspepsia/ indigestion/ abdominal pain Diarrhoea Constipation Total number of patients with one or more AE
Placebo (« = 20)
5 mg
10 mg (« = 23)
20 mg 50 mg (« = 22) (« = 22)
6 (30%)
7 (33%)
9 (39%)
9 (41%)
5 mg (« = I7)
lOmg (n = 22)
20mg 50mg (n = 17) (« = 35)
II (50%)
1
2
4
4
4 0 0
4 4 1
5 2 4
9 4 1
5 (29%)
10 (45%)
10 (59%)
15 (43%)
Expressed in patient years, the total treatment duration for the 108 patients was 31.3 years. The exposure to 50 mg was double that of the other groups at 8.05 years in comparison to the number experienced at the 10 mg, because patients on placebo converted to ibandronate 20 mg and 50 mg dose levels (13 of 41 [32%] vs. 29 of 50 mg after the first four weeks. Compliance appeared 67 [43%]). In the three-month follow-on study all doses to be good and the serum levels obtained in 65 patients showed similar tolerability (Table 5); patients who on day 21 of ibandronate reflected the administered dose switched from placebo to 50 mg had the same incidence (Table 4). The ibandronate serum level was below the of GI adverse events as those who started on 50 mg. lower limit of detection in 15 (23%) of patients (seven at Nine (8%) patients stopped treatment within the first 5 mg, seven at 10 mg and one at 20 mg). month due to GI intolerability but these patients were In general, ibandronate was well tolerated. One or evenly distributed across the five treatment groups. GI more gastrointestinal (GI) adverse events occuring in tolerability may have been adversely affected by conthe first month of treatment were reported by six (30%), commitant administration of non-steroidal anti-inflamseven (33%), nine (39%), nine (41%) and eleven (50%) matory agents although the study numbers were too patients at the placebo, 5, 10, 20 and 50 mg dose levels small to confirm this clinical impression. There was no respectively (Table 5). One patient on ibandronate 20 mg difference in non-GI adverse events between groups. developed severe dysphagia with oesophageal ulceration Although individual patients reported improvements clearly demonstrated on barium swallow examination in bone pain and were able to reduce their analgesic approximately one week after starting treatment. intake, no significant effects of treatment over time or The incidence of GI adverse events in the 5 mg treat- between the treatment groups were demonstrated. ment group was comparable to that experienced by the Twenty-three patients who reported clinical benefit and placebo group, and slightly less (but not significantly so) good tolerability at the end of the four-month study
315 period requested continued treatment with oral ibandronate in the context of named patient supplies for 3-36+ months. These requests were evenly spread across the treatment groups. Discussion On the basis of changes in biochemical markers of the rate of bone resorption, this study of oral ibandronate has clearly demonstrated efficacy at doses which were generally well tolerated. A four-week treatment reduced the excretion of calcium and collagen crosslinks in the urine with a clear dose response relationship; 5 mg was the minimum effective dose and the largest changes were seen at the 20 mg and 50 mg dose levels. The reduction in urinary calcium excretion was the primary endpoint of the study since this was the most widely used indicator of bisphosphonate effects on calcium metabolism at the time the study was initiated. The fasting urinary excretion of calcium integrates both resorption and formation and it thus provides a marker of net resorption. Recent studies have shown that urinary calcium correlates poorly with the collagen crosslink measurements of bone resorption due to the influence of acute changes in parathyroid hormone induced by bisphosphonates [14, 15, 24]. In recent years more sensitive and specific markers of bone resorption have been developed which we used as secondary end-points [14, 15, 22]. The excretion of the collagen breakdown products pyridinoline and deoxypyridinoline and the protein bound fragments identified by the Ntx and CTX assays confirmed a clear doseresponse relationship with, as seen in previous bisphosphonate studies [22, 23], the greatest changes occuring in the urinary levels of the protein bound crosslinks. An ANalysis of COVAriance model showed that for most comparisons the 20 mg and 50 mg doses were more effective than the 5 mg and 10 mg doses. A much larger study would be necessary to define the optimum dose with more precision. As we have observed in previous studies, there were no significant differences in the biochemical responses observed in the breast cancer patients compared with the other tumour types (data not shown) [24, 25]. As expected there were occasional patients who could not tolerate oral ibandronate due to gastrointestinal adverse events. A slight excess of GI adverse events occured at the 10 mg, 20 mg and 50 mg dosages but the number of patients who discontinued treatment because of adverse events was similar in all groups including placebo. GI adverse events were usually reported in the first 14 days of treatment such that the identification of patients unable to tolerate oral ibandronate was relatively straightforward. Apart from the one patient with oesophageal ulceration, all GI adverse events resolved on discontinuation of therapy within 24-48 hours. The subjective benefits of oral ibandronate were difficult to demonstrate in this study, despite a relatively
large cohort of patients receiving treatment unconfounded by other anticancer treatments. Undoubtedly individual patients reported significant and occasionally long-lasting improvement in pain but no consistent effect could be demonstrated. Reports of pain relief were unrelated to the dose of ibandronate or the changes observed in bone resorption markers. This is in contrast to the very clear effects of intravenous pamidronate [24], clodronate [26] and zoledronate [27] in reducing bone pain and analgesic consumption, and improving mobility and quality of life through effective reversal of the tumour induced increase in bone resorption rates [24, 28]. Interestingly, although a reduction in skeletal related events has been demonstrated with oral bisphosphonates [6-8], acute pain relief in metastatic bone disease has also not been convincingly demonstrated with either oral clodronate [29] or pamidronate [10]. For acute relief of severe bone pain, high doses of intravenous bisphosphonate appear to be necessary. In conclusion ibandronate is a generally well tolerated oral amino-bisphosphonate with rapid and clear effects on surrogate markers of bone resorption. The 20 mg and 50 mg tablets would appear to be the most promising doses to take forward into phase III development in metastatic bone disease.
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Received 1 October 1998; accepted 13 January 1999.
Correspondence lo: Dr R. E. Coleman YCR Department of Clinical Oncology Weston Park Hospital Sheffield S10 2SJ UK