P4-16-05: A Randomized Phase 2 Study of a Loading Dose of Ibandronate in Patients with Bone Metastases from Breast Cancer.
Authors: Ritchie DM , Bray C , Canney P 
Published: June 2012

Abstract
Bisphosphonates have proven efficacy in reducing skeletal complications in metastatic breast cancer. Potent third generation bisphosphonates are more effective but the dose limiting toxicity is usually renal. Ibandronate is a 3rd generation bisphosphonate available in oral and intravenous form which offers many clinical advantages in ease of administration and lack of renal toxicity. A dose-response effect has been observed between 2mg and 6 mg IV doses and there is a single study suggesting that higher dosing (4 mg IV daily for 3 days) is tolerable and effective. A steady state of oral ibandronate is achieved at 8 days with oral administration but time to response is not known. In trials so far, IV ibandronate 6mgs appears safe. Due to lack of renal toxicity there is potential for further escalation of IV ibandronate. The objective of this study was to establish if an IV loading dose can improve efficacy and time to biochemical response compared to oral standard therapy and to assess the safety of a higher IV dose of ibandronate.
Methods and Patients: This was an open randomised phase II study conducted on patients with bone metastases from breast cancer comparing IV ibandronate 12 mg on day 1 followed by oral ibandronate 50 mgs daily (Arm A) with standard oral therapy of 50 mgs daily from day 1 (Arm B). The primary study end-point was the percentage reduction in serum CTX from baseline by day 5 on study, secondary end- points were the percentage reduction of bone turnover markers including serum CTX from baseline end of week 8 and percentage reduction in urine NTX from baseline to day 5 on study and baseline to end of week 1–8. Bone pain was recorded by Brief Pain Inventory. Patients had metastatic breast cancer with proven bone metastases, no previous treatment with bisphosphonates or other bone directed therapy within 6 months and no change in systemic therapy within a 3 months preceding trial therapy. Sample size of 22 patients in each arm was calculated to give a 90% chance detecting a 20% difference in average percentage reduction between the IV and oral arms.
Results: Seventeen patients were randomised to each study arm. A more rapid change in bone turnover markers was demonstrated in patients recieving the 12 mg loading dose of ibandronate. There was a 15.8% greater reduction of serum CTX in Arm A compared with Arm B at day 5, p=0.005. The percentage reduction of serum PINP at day 5 was also greater in Arm A, p=0.002. Over the 8 week period of study there was no overall significant difference in bone turnover markers. All patients had pain at study entry, median baseline pain severity scores were 3 in study arm and 4 in controls. Average bone pair score remained higher in treatment arm B at the end of 8 weeks. There were no additional adverse side-effects following administration of 12 mg of IV ibandronate and no evidence of additional renal toxicity. Conclusion: A 12 mg dose of IV ibandronate can be safely administered without additional renal toxicity. A rapid reduction in bone turnover markers is demonstrated within 5 days of IV loading dose of ibandronate. Potential exists for dose escalation of ibandronate. The clinical benefit of a more rapid reduction in bone turnover markers is unknown.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-05.