Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease

R. E. Coleman 1 2 O. P. Purohit 1 2 C. Black 1 2 J. J. F.Vinholes 1 2 K. Schlosser 1 2 H. Huss 1 2 K. J. Quinn 1 2 J. Kanis 0 1 2 0 Department of Human Metabolism & Clinical Biochemistry, Royal Hallamshire Hospital , Sheffield , UK 1 ' Yorkshire Cancer Research Department of Clinical Oncology. Weston Park Hospital , Sheffield , UK; ~Boehringer Mannheim Therapeutics , Livingstone, Scotland and Mannheim , Germany 2 Dr R. E. Coleman YCR Department of Clinical Oncology Weston Park Hospital Sheffield S10 2SJ UK Summary were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At Background: Bisphosphonates are an important component of the 50 mg dose level, the percentage reductions from baseline the treatment of metastatic bone disease but more potent, oral in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% formulations are required to improve the effectiveness and 80% and 74% respectively. convenience of treatment. An oral formulation of the new One or more gastrointestinal (GI) adverse events occurring bisphosphonate, ibandronate (BM 21.0955) has recently been in the first month of treatment were reported by six (30%), developed. seven (33%), nine (39%), nine (41%) and eleven (50%) patients Patients and methods: One hundred ten patients with bone at the placebo, 5,10, 20 and 50 mg dose levels respectively. One metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were patient (20 mg dose) developed radiographically confirmed recruited from a single institution to this double blind placebo- oesophageal ulceration. GI tolerability may have been adversely controlled evaluation of four oral dose levels (5, 10, 20 and 50 affected by concommitant administration of non-steroidal antimg) of ibandronate. No changes in systemic anti-cancer treat- inflammatory agents. Nine (8%) patients stopped treatment ment were allowed in the month before commencing treatment within the first month due to GI intolerability but these patients or during the study period. After an initial four-week tolerabil- were evenly distributed across thefivetreatment groups. There ity phase, patients could continue on treatment for a futher was no difference in non-GI adverse events between groups. three months without unblinding; patients initially allocated to Conclusions: Oral ibandronate has potent effects on the rate placebo received ibandronate 50 mg. The primary endpoint of bone resorption at doses which are generally well tolerated. was urinary calcium excretion (UCCR). Bone resorption was Further development is appropriate to evaluate the effects of also assessed by measurement of pyridinoline (Pyr), deoxy- long-term administration in the prevention of metastatic bone pyridinoline (Dpd), and the N-terminal (NTX) and C-terminal disease and the management of established skeletal metastases. (Crosslaps) portions of the collagen crosslinking molecules. - Results: Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients 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. 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 Female Disease (...truncated)