Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. Skeletal complications due to metastatic disease include bone pain, spinal cord compression and pathological fractures (1).
Bisphosphonates are effective inhibitors of osteoclastic bone resorption and have demonstrated therapeutic efficacy in the treatment of tumor-induced hypercalcemia (TIH) and cancer-related bone disease associated with multiple myeloma and breast cancer (2-13).. The precise mechanism(s) by which bisphosphonates inhibit osteoclast function is not fully understood but may include direct toxic effects on mature osteoclasts, an inhibition of osteoclast production from precursor cells and impairment of osteoclast chemotaxis to sites of bone resorption (14-16). Osteoclasts are specialized bone cells which erode mineralized bone by secreting acids and lysosomal enzymes. The lytic bone destruction associated with malignancy develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone (17-19). The osteoclastic activating factors released by tumor cells include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines (20-23). The malignant activation of osteoclasts results in disruption of normal bone remodeling wherein the equilibrium between bone resorption and bone formation is shifted towards increased bone resorption. Thus, the predominant role of the osteoclast in the pathogenesis of bone destruction and the inhibitory effects of bisphosphonates on osteoclast function have formed the rationale for the use of bisphosphonates in the treatment of osteolytic bone metastases. The common role, regardless of tumor type, of osteoclasts as mediators of bone destruction in metastatic skeletal disease is indicated by the effectiveness of bisphosphonates in the therapy of TIH arising from any type of cancer (2-6). Recent studies have shown that therapy with the bisphosphonate pamidronate (Aredia®) combined with anti-neoplastic therapy significantly reduces the proportion of patients having skeletal complications due to the lytic bone disease associated with multiple myeloma and breast cancer compared to anti-neoplastic therapy alone (11,12).
Zoledronate, a third generation bisphosphonate, is 2-(imidazol-l-yl-hydroxyethane- 1, 1 -bisphosphonic acid) in the form of its monohydrate. The compound is characterized by a side chain including an imidazole ring. Zoledronate is a more potent inhibitor of osteoclasts than earlier bisphosphonates. In the 1 ,25-dihydroxyvitamin D3-induced hypercalcemia model in thyroparathyroidectomized rats, zoledronate was 850 times more potent than pamidronate and more than four orders of magnitude more potent than either clodronate or etidronate (24). In addition, zoledronate was two orders of magnitude more potent than pamidronate in inhibiting release of calcium from mouse calvaria in vitro, irrespective of the stimulus [1 ,25(OH}-,D3, parathyroid hormone (PTH), PTHrP, prostaglandin-E2, or IL-i B] (24). In addition, zoledronate has little effect on bone mineralization in vitro and has the largest therapeutic ratio between the desired inhibition of calcium resorption and the unwanted inhibition of mineralization in vitro of all bisphosphonates (24).
Zoledronate has been evaluated for acute and chronic toxicity in rats and dogs (25). Toxicity to the gastrointestinal tract, liver, kidneys, lymphatic system and the musculature was observed only at doses far above those which are effective in suppressing osteoclasts. Moreover, bolus intravenous (i.v.) infusions of zoledronate were used in dog studies and found to be tolerated as well as oral or subcutaneous administration. Zoledronate has been evaluated for acute and chronic toxicity in rats and dogs (25). Toxicity to the gastrointestinal tract, liver, kidneys, lymphatic system and the musculature was observed only at doses far above those which are effective in suppressing osteoclasts. Moreover, bolus intravenous (i.v.) infusions of zoledronate were used in dog studies and found to be tolerated as well as oral or subcutaneous administration.
Phase I clinical studies have provided evidence of the potency of zoledronate to inhibit osteoclastic bone resorption. Doses of zoledronate 0.5 - 3 mg have been shown to be effective in the treatment of TIN (26). Similar doses have also been shown to significantly reduce the levels of bone resorption markers in patients with bone metastases from a variety of tumor types (27). In addition, data from an on-going phase II study indicate that long-term therapy with i.v. zoledronate at doses of up to 8 mg is well tolerated as a 5-minute infusion (28).
The primary objective:
To demonstrate the non-inferiority of i.v. zoledronate 4 mg and/or 8 mg to Aredia 90 mg in preventing skeletal-related events (SREs) in patients with cancer-related bone lesions due to multiple myeloma or breast cancer. In the event that non-inferiority is demonstrated, the possible superiority of zoledronate 4 mg and/or 8 mg over Aredia 90 mg will be tested.
SREs are defined as:
The primary efficacy variable is the proportion of patients experiencing at least one of the above SREs.
The secondary objectives:
To compare the effects of i.v. zoledronate 4 mg and/or 8 mg to Aredia 90 mg with respect to
safety and tolerability and to the following efficacy parameters:
To prevent bias in the assessment of the clinical efficacy and safety parameters, the study will be randomized and will be conducted in a double-blind fashion in regard to an individual patients assignment to a treatment group. An individual patients assigned treatment group will be known only to the pharmacist at the center where that patient is receiving treatment.
The primary purpose of the study is to assess the efficacy of i.v. zoledronate (4 or 8 mg) compared to i.v. Aredia 90 mg to prevent SREs associated with cancer-related bone disease in patients with multiple myeloma or breast cancer. SREs are objective clinical endpoints and include radiation therapy to bone, surgery to bone, spinal cord compression and pathologic fracture.
The trial is powered to demonstrate the non-inferiority of zoledronate 4 mg and/or 8 mg to Aredia 90 mg in terms of the proportion of patients experiencing SREs. The non-inferiority margin is set at 8% which is approximately 60% of the difference that was seen between the Aredia and placebo arms in previous trials in patients with multiple myeloma or breast cancer (11,12). However, the possibility that zoledronate (4 mg and/or 8 mg) will be significantly superior to Aredia 90 mg cannot be excluded.
Use of Aredia and zoledronate in cancer-related bone disease
Progression of cancer-related bone disease, resulting in the occurrence of SREs, invariably occurs despite the use of anti-cancer therapies such as chemotherapy and hormonal agents. The prevention of SREs secondary to bone destruction in patients with multiple myeloma and breast cancer using Aredia, a second generation bisphosphonate, is a therapeutic advance which has improved the quality of life of these patients (11,12). Zoledronate, a third generation bisphosphonate, is an extremely potent inhibitor of osteoclastic bone resorption and may allow a further reduction in the morbidity associated with cancer-related bone disease over that which has been demonstrated with Aredia. Based on the positive results of the above studies, Aredia is now widely accepted as an important therapy in the treatment of patients with cancer-related bone
disease due to multiple myeloma and breast cancer and it was therefore considered inappropriate to include a placebo-treated arm in this present study.
Dose and schedule
There are three treatment arms in this study: zoledronate 4 mg, zoledronate 8 mg and Aredia 90 mg, each to be administered by i.v infusion. Aredia at a dose of 90 mg every 3-4 weeks has been shown to reduce the incidence of SREs in patients with multiple myeloma and breast cancer (11,12) and is the approved dose for the treatment of these conditions in many countnes.
Two zoledronate treatment groups (4 mg and 8 mg) are included because the optimal therapeutic dose of zoledronate is not known. A phase I study of zoledronate in TIH in 33 patients (CJ/HC 1) demonstrated that a> 90% complete response rate was achieved with zoledronate doses ranging from 0.5-3 mg. Response rates of this magnitude are reliably achieved with Aredia 90 rng (6).
This suggests that a zoledronate dose of around 2 mg is equivalent to Aredia 90 mg (26). An ongoing randomized, double-blind phase II study (Protocol 007) of zoledronate treatment for metastatic bone disease has enrolled more than 250 patients and suggests that up to nine monthly cycles of 5-minute i.v. infusions of up to 4 mg of zoledronate are well tolerated, with no drug-related serious adverse events reported to date. Thus, zoledronate 4 mg appears to be sa.fe and may represent a dose which exceeds the ability of Aredia 90 mg to inhibit osteoclastic bone resorption by a factor of approximately two. Similarly, zoledronate 8 mg may exceed the bone resorption inhibitory capacity of pamidronate 90 mg by at least 4-fold. This may be parti~ularly important because data from a previous study suggest that higher doses of Aredia reliev~ bone pain in cancer patients more effectively than do lower doses (29).
A recent phase I study (Protocol 003) of three consecutive monthly zoledronate infusions in patients with bone metastases indicates that doses of up to 8 mg are well tolerated as 5-minute i.v. infusions (28). Furthermore, the 8 mg dose was associated with the greatest inhibition of markers of bone resorption and the greatest decrease in pain scores when compared to lower doses, including 4 mg. The 8 mg dose was not included in the core phase of Protocol 007, but has been included in the extension phase. Data from approximately 20 patients treated thus far in phase 1111 studies indicate that the 8 mg dose is well tolerated. These data are consistent with repor~s from other bisphosphonates which indicate that the use of these compounds is associated with f4w side effects.
A 3-4 weekly schedule has been selected for administering both zoledronate and Aredia. Data from the phase I study (Protocol 003) indicated that pain scores began to deteriorate four weeks after zoledronate administration in about half the treated patients (28). Furthermore, Are~lia has been administered safely on a 3-4 weekly cycle in a large study in breast cancer patients (12). Finally, a 3-4 weekly schedule corresponds to the mode of administration of many chemotherapy regimens.
Tumor and bone response
Overall disease progression data will provide information as to whether the treatment groups are comparable in terms of overall tumor response. Although zoledronate and Aredia are not believed to exert direct anti-cancer effects, they are osteotropic drugs which inhibit tumor-induced skeletal destruction. Thus, a separate analysis to determine time to progression of bone lesions will be done. It is recognized that these two time points may be identical in many patients because progression of bone lesions is often the first manifestation of disease progression. The clinical course of bone lesions will be followed using bone scans and bone surveys which will be read by a central radiologist. Bone scans will be performed every six months in breast cancer patients only and bone surveys every three months in both patient groups in order to provide sufficient data points to detect a minimum difference of three months in time to progression. Non-skeletal sites of tumor are to be followed for overall tumor response by appropriate radiographic studies. These studies are to be obta.ined every three months and will also be read by a central radiologist.
This protocol requires all patients to receive 500 mg of calcium supplements and a multi-vitamin tablet (containing 400-5 00 IU of vitamin D), orally, once daily, for the duration of administration of study medication, including the optional extension phase. This therapy is given to blunt the compensatory rise in PTH levels which occurs secondary to the transient hypocalcemia caused by the administration of bisphosphonates. PTH may act as an osteoclast activating factor and therefore preventing this rise may be beneficial (30). These supplements will be discontinued if the patient develops TIH and when the patient discontinues study medication.
The patients will be enrolled in 250 centers in approximately 20 countries. A total of 1470 eligible patients will be enrolled, 490 in each of the three treatment groups. Patients discontinuing trial treatment before 12 months will not be replaced. The target population comprises patients with cancer-related bone lesions due either to multiple myeloma or breast cancer.
Page Last Updated 08/20/2003 08:39:46 PM