Regular dosing of zoledronic acid maintains continuous suppression of osteolysis in patients with malignant bone disease

ABSTRACTS / Bone 42 (2008) S17–S110

197 Prospective Observational Study (ZORES Study) on analysis of genetic mutations and enzymatic activity of Farnesyl Pyrophosphate Synthetase (FPPS) as predictive factor of resistance to amino-bisphosphonates (N-BP) in patients with bone metastases from solid tumors Daniele Santini a, Sara Galluzzo a, Bruno Vincenzi a, Silvia Angeletti a, Michele Caraglia b, Giordano Dicuonzo a , Giuseppe Tonini a a Medical Oncology, University Campus Bio-Medico, Rome, Italy b Experimental Oncology Department, National Institute of Tumours Fondazione G. Pascale, Naples, Italy Background: N-BP are used to prevent and delay the incidence of skeletal-related events (SREs) in patients with metastatic bone disease. Moreover, all clinical studies have shown that a percentage of patients does not benefit from this drug, presenting a kind of resistance to N-BP action. Molecular mechanisms at the base of this resistance are not known. FPPS has been identified as the molecular target of N-BPs. The structure of human FPPS has been determined and the important residues in the catalytic site responsible for its activation have been characterized. The structure of the gene, both the promoter region and the catalytic region, are known. Study design: 300 consecutive patients with bone metastases from prostate cancer, breast cancer and from other solid tumours will be included in the study. All patients will receive, for the first time, zoledronic acid (ZA) 4 mg every 28 days. A control group composed by 100 healthy donors matched by age and sex will be included in the study analysis. Anticoagulated peripheral blood samples will be drawn before (basal time), 28 days and 2, 3, 6, 9, 12, 15, 18, 24 months after ZA treatment. The study will be carried out for 24 months, in two different phases of 12 months each. During phase 1, our purpose is to reach the following objectives: 1) sequencing the codying gene for FPPS to identify the presence and the incidence of genetic mutations in the NBPs -binding site and in the promoter of FPPS; 2) measuring, at each time point, the expression and the enzymatic activity of FPPS. During phase 2, our purpose is to reach the following objectives: evaluate if there are statistical correlations among the presence/absence of genetic mutations in the ligand-binding site and in the promoter of FPPS, the variations of concentration and enzymatic activity of FPPS and the following parameters of clinical efficacy of ZA: (a) variations in plasmatic and/or urinary bone resorption (NTX and CTX) and bone formation marker (OPG, BALP) concentrations after ZA treatment; (b) incidence of patients with ≥ 1 Skeletal-Related Events (SREs), median time to first SRE, median number of SREs per patient; (c) survival data: median survival and median time to skeletal progression. Predicted results: Identify “genetic” and “non-genetic” causes of resistance to N-BP activity in cancer population. Preliminary results will be presented during the meeting. doi:10.1016/j.bone.2007.12.207

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198 Renal safety profile of ibandronate 6mg infused over 15 or 60 min in breast cancer patients with bone metastases F. Schütz a, R. von Moos b, C.B. Caspar c, R. Angst d, R. Inauen b, R. Greil e, J. Ziegler f, M. Pecherstorfer g a Universitätsklinikum Heidelberg, Heidelberg, Germany b Kantonsspital Graubünden, Chur, Switzerland c Kantonsspital Baden, Baden, Switzerland d Kantonsspital St. Gallen, St. Gallen, Switzerland e Universitätsklinikum Salzburg, Salzburg, Austria f Roche Pharma AG, Grenzach-Wyhlen, Germany g Wilhelminenspital, Wien, Austria Background: The recommended intravenous ibandronate dose is 6mg, given every 3–4 weeks. Phase III trials with 6mg ibandronate infused over 60 min, have shown that renal safety is comparable to placebo. A shorter infusion time of 15 min is more convenient for patients. This randomized phase III study investigated the renal safety of the non-cyclic mono-aminobisphosphonate ibandronate related to infusion time. Patients and methods: 127 patients with breast cancer and metastatic bone disease received ibandronate 6mg every 3– 4 weeks for 6 months in this non-blinded, prospective, randomized multicenter study. Patients were recruited by centers in Switzerland, Austria, and Germany, and were stratified according to previous treatment and the presence or absence of visceral metastases. All patients had serum creatinine levels within normal limits and calculated creatinine clearance 50 ml/ min. 101 patients received ibandronate 6 mg over 15 min and 26 patients over 60 min. The primary endpoint was the percentage of patients with an increase in serum creatinine from baseline of 44.2 μmol/l (0.5 mg/dl) at any study visit. Secondary endpoints included detection of tubular and glomerular markers of kidney damage. Results: A total of 81% of the patients in the 15-min infusion group and 77% in the 60-min infusion group completed the treatment period. There were no significant changes in mean serum creatinine values, mean calculated creatinine clearance, or mean values of serum glomerular and tubular markers in any of the groups at any time. Conclusion: Like the standard 60-min infusion, the rapid 15-min infusion of ibandronate 6 mg in patients with breast cancer and bone metastases was well-tolerated. There were no significant differences in renal safety parameters in both groups. This study provides the basis for using ibandronate 6 mg via 15min infusions in clinical practice. doi:10.1016/j.bone.2007.12.208

199 Regular dosing of zoledronic acid maintains continuous suppression of osteolysis in patients with malignant bone disease Horst Schran, Christina Ravera, Andrej Skerjanec, Manon Boisclair Novartis Pharmaceuticals Corporation, East Hanover, USA

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ABSTRACTS / Bone 42 (2008) S17–S110

Background: Zoledronic acid (ZOL) has demonstrated significant efficacy in preventing skeletal-related events in patients with malignant bone disease (MBD). Monthly ZOL potently reduces levels of biochemical markers of osteolysis (e.g., C-terminal and N-terminal peptides of type I collagen [CTX and NTX, respectively]) in this setting. However, until prospective data on bone marker changes with alternative treatment scheduling become available from ongoing trials, data from early clinical studies may provide insight on the impact of changes in ZOL dose levels and frequency. Material and methods: One marker data were evaluated from 3 pharmacology trials in patients with MBD: Study A— patients with varying renal function (n = 19; 4 mg ZOL q 4 wk, up to 2 years); Study B—patients with normal renal function (n = 36; dose ranging 4–16 mg ZOL q 4 wk, up to 2 years); Study C— patients with severe renal impairment (n = 8 without hemodialysis; single dose of 1–2 mg ZOL based on the creatinine clearance rate pharmacokinetic model used in the prescribing information; achieves the same AUC exposure as that of 4 mg ZOL in patients with normal renal function). Urinary NTX and CTX levels were measured in all studies before and after ZOL. Results: In Study A, 4 mg ZOL caused a strong initial decrease in urinary levels of both CTX and NTX vs baseline (means of ∼80% and ∼50%, respectively). CTX levels remained N 30% below baseline and NTX levels remained N 40% below baseline throughout the study in patients with all levels of renal function. Similarly, in Study B, ZOL significantly reduced NTX levels vs baseline (P = .001). At the 4-mg dose level, ZOL reduced mean NTX levels by 58% to 76% below baseline throughout treatment. In Study C, a single dose of ZOL produced nadir decreases of 54% (CTX) and 43% (NTX) vs baseline. Mean decreases vs baseline by visit (4= days 9–11; 5 = days 26– 30; 6 = days 54–58; end = days 82–86) for CTX were: 4, −51%; 5, −40%, 6, −24%; end, −24%. Mean decreases vs baseline by visit for NTX were: 4, −32%, 5, −28%; 6, −3%, end, −3%. Conclusions: These data illustrate the effectiveness of ZOL for reducing levels of osteolysis in patients with MBD. Consistent with the approved dosing regimen, ZOL q 4 wk resulted in continuous suppression of NTX and CTX. However, NTX and CTX began to approach baseline levels after approximately 4 wk in patients who received only 1 dose of ZOL. These data underscore the importance of adherence to the approved dosing schedule for ZOL. Horst Schran; Novartis Pharmaceuticals Corporation; Employee of Novartis Pharmaceuticals Corporation. doi:10.1016/j.bone.2007.12.209

200 Sagopilone (ZK-EPO) inhibits bone destruction and tumor burden more efficiently than paclitaxel in a mouse model of established breast cancer bone metastasis Anne Strube, Elizaveta Stepina, Ulrich Klar, Peter Hauff, Jens Hoffmann, Sanna-Maria Käkönen Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany

The preferential site of breast cancer metastasis is bone. Taxanes are currently among the most commonly used drugs in the treatment of metastatic breast cancer. In this study, we have demonstrated that sagopilone, the first fully synthetic third generation epothilone in clinical development, is more effective than paclitaxel in a breast cancer bone metastasis model. We examined the therapeutic effect of sagopilone and paclitaxel on tumor-induced osteolysis and tumor burden in athymic nude mice inoculated intracardially with MDA-MB-231(SA)/luc human breast cancer cells. On day 12 after tumor cell inoculation, animals were randomized into treatment groups according to the lesion size as measured by radiography. A single dose of sagopilone was administered on day 13 (10 mg/ kg, i.v.). Paclitaxel was given once daily on days 13–17 (9 mg/ kg, i.p.). At sacrifice (day 23), bone lesions were measured using radiography and micro-CT. Tumor cell dissemination was detected by bioluminescence imaging and histomorphometry. The effect of compounds on bone resorption was determined by measuring TRACP5b in serum and by counting the number of osteoclasts on tumor–bone interface by histomorphometry. Both sagopilone and paclitaxel treated animals had less tumorinduced cachexia and paraplegia compared to the vehicle group. Radiographic analysis revealed that further tumor-induced bone destruction was merely reduced by paclitaxel, whereas sagopilone completely prevented it. Sagopilone-treated animals had also higher bone volume compared to other groups as measured by micro-CT. Furthermore, the serum TRACP5b concentration, as well as the number of osteoclasts were reduced in sagopilone-treated animals when compared to the vehicle group. A marked effect of sagopilone on tumor growth in bone was observed as reduced bioluminescence signal intensity in vivo. This was confirmed by histomorphometry in H?E-stained bone sections. Paclitaxel had no significant effect on tumor growth in bone. Sagopilone had significantly better effect on reducing bone destruction and tumor burden when compared to paclitaxel in a mouse model of established breast cancer bone metastasis. These data suggest sagopilone as a potential antimetastatic agent in the treatment of breast cancer bone metastasis. Anne Strube; Bayer Schering Pharma AG; PhD student grant. doi:10.1016/j.bone.2007.12.210

201 Zoledronic acid induces caspase dependent apoptosis in renal cancer cell lines Anders Ullén a, Lena Lennartsson a, Karl-Mikael Kälkner a, Per Sandström a, Bo Lennernäs b, Stig Linder a, Sten Nilsson a a Oncology-Pathology, Radiumhemmet, Karolinska Hospital and Institute, Stockholm, Sweden b Sahlgrenska Academy University, Sahlgrenska University Hospital, Gothenburg, Sweden Introduction: Renal cancer (RC) is characterized by its poor sensitivity to systemic treatment. Tyrosine kinase