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 o (...truncated)