A randomized, double-blind, placebo controlled, Phase III trial evaluating the palliative benefit of either continuing pamidronate or switching to second-line zoledronic acid in breast cancer patients with high risk bone metastases
You are being asked to consider taking part in a research study because you are a woman with breast cancer that has spread to bone (bone metastases) and you are at risk of developing complications in the future. These complications can include fractures, high calcium levels, or pain in your bones that may need treatment with radiation therapy or surgery. You are currently receiving a type of drug called a bisphosphonate (intravenous pamidronate). In this study, participants will undergo a blood test to determine the amount of activity in their bones due to the bone metastases. Those with a high activity score on their blood test or with bone pain or previous bone complications will be randomly selected to either be treated with a newer bisphosphonate called zoledronic acid (Zometa) or continue on their current therapy (pamidronate).
Zoledronic Acid is a widely approved drug in Canada, the United States and Europe for the treatment of breast cancer metastases spread to the bones. It is approved by the Food and Drug Administration (FDA, United States) and Health Canada for the treatment of bone metastases that are causing high blood calcium levels.
The purpose of this study is to evaluate whether zoledronic acid given intravenously once a month for three months can improve the symptoms of bone metastases in women who have previously received pamidronate, compared to continuing with their previous bisphosphonate treatment (pamidronate).
Symptoms of bone metastases can vary. Some symptoms may include bone pain (which is the most common), weakness, numbness, trouble urinating, nausea and general physical discomfort. The primary goal of the study is to see if zoledronic acid leads to significant improvement in blood and urine tests (representative of decreased cancer activity), decreasing pain, symptom control and possibly a decreased risk of future bone complications.
- To compare the proportion of high-risk metastatic breast cancer patients with bone metastases that will achieve a decrease in sCTX (surrogate for decrease risk of SREs) in the zoledronic and pamidronate treatment arms.
- To determine the proportion of high-risk metastatic breast cancer patients that will achieve a significant improvement in palliative response (defined as a two unit drop in their worst pain score, based on a brief pain inventory questionnaire for two consecutive measurements at least one month apart) in the zoledronic and pamidronate treatment arms.
- To assess whether a drop in sCTX one week post infusion of zoledronic acid is a predictor of pain benefit at week 12. We will test the strength of the association in sCTX drop (any drop from baseline level) at week 1 and palliative response when measured at week 12, using the validated BPI and FACT-BP questionnaires.
- To assess overall pain control between the experimental group and the control group over the 12 week study period using the validated BPI and FACT-BP questionnaires.
We will collect data to compare overall opiate analgesics use over the 12-week period measured as an oral Morphine Equivalent Dose (MED), quality of life measures (FACT-G Ver 4), toxicity (using NCI-CTC toxicity score) and subsequent SREs between the zoledronic acid and pamidronate arms. Serum and urine will also be stored at each time point for future correlative studies.
Bone is the most common site of metastatic spread in breast cancer. These patients are at a high risk of skeletal related events (SREs) such as: fractures and spinal cord compression. Treatment is with bisphosphonates (the most common being pamidronate) which is given intravenously every 3-4 weeks irrespective of an individual patients risk for a SRE. This “one size fits all’ approach is no longer acceptable in the era of personalized medicine.
This is a prospective, randomized, double-blinded, placebo-controlled study Phase III study. This study aims to explore whether we can optimize the care of those patients with the highest risk disease by switching them to a more potent bisphosphonate (zoledronic acid). Our primary objective is to compare the proportion of high-risk patients with bone metastases that will achieve a decrease in sCTX (surrogate for decrease risk of SREs) in the zoledronic acid and pamidronate treatment arms. High-risk will be defined as fulfilling one or more of the following criteria: elevated sCTX (>400ng/L) and/or bone pain and/or a prior SRE and/or progression of bone disease (by imaging) despite at least 3 months of pamidronate therapy. Patients who meet the eligibility criteria, will be randomized to receive 3 cycles of intravenous zoledronic acid (4mg intravenously over 15 minutes) or to continue their monthly pamidronate (90mg intravenously over 1-2 hours). Both treatments will be given at 4 week intervals.
Patients will be stratified according to whether or not they have an elevated sCTX or have had a SRE prior to study entry. Patients will be randomized using a stratified block design. In order for the study to be double-blind, patients will receive two infusions simultaneously, at each study visit, one of the active drug and another of the placebo. After completing 3 cycles of study treatment, patients will resume their monthly intravenous pamidronate infusions as per current standard of care. Patients will be in the study for 3 months (5 visits total: baseline, 1 week, 1 month, 2 months, 3 months).
We predict that patients who are at high risk of a SRE will experience a decrease in the marker of bone breakdown (sCTX) at week 12 if switched to zoledronic acid. This is in contrast to those patients who continue on intravenous pamidronate therapy which is the current standard of care. We anticipate a drop in sCTX levels will be correlated with improved pain, improved patient’s quality of life and possible a reduction of further SREs.