A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid (Zometa) in the Treatment of Bone Metastases in Subjects with Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

Besides systemic antineoplastic treatment, radiation therapy to bone has been
the mainstay of controlling metastatic bone disease. Other widely used
palliative treatments of metastatic bone disease are bisphosphonates, which
have been shown to reduce the incidence of SREs, bone pain, and hypercalcemia
in patients with bone metastasis in several randomized clinical trials. While
they have proven to be good inhibitors of bone resorption, it has become clear
that their anti-resorptive activity resides in their ability to inhibit
osteoclast activities, rather than their physicochemical properties. There is
previous clinical experience with Denosumab in the treatment of prevention
osteoporosis, and cancer associated bone diseases.

To determine if denosumab is non-inferior to zoledronic acid with respect to
the first on-study occurrence of a skeletal related event (SRE) in subjects
with advanced cancers and bone metastases (or lytic bone lesions from multiple
myeloma).

SRE is defined as pathologic fracture, radiation therapy to bone, surgery to
bone, or spinal cord compression.

This is an international, phase 3, randomized, double-blind, active controlled
study comparing denosumab with zoledronic acid in the treatment of bone
metastases in subjects with advanced cancer or multiple myeloma. Approximately
1690 subjects will be randomized in a 1:1 ratio to receive either denosumab,
administered at a dose of 120 mg SC every 4 weeks (Q4W), or zoledronic acid,
administered IV at a dose of 4 mg (equivalent creatinine clearance-adjusted
dose in subjects with baseline creatinine clearance * 60 mL/min) as a single,
minimum 15-minute infusion Q4W, in a blinded manner. Each subject will receive
either an SC injection of denosumab and an IV infusion of zoledronic acid
placebo Q4W, or an SC injection of denosumab placebo and an IV infusion of
zoledronic acid Q4W until approximately 745 subjects have experienced an
on-study SRE. SRE is defined as pathologic fracture, radiation therapy to bone,
surgery to bone, or spinal cord compression.
It is strongly recommended that all subjects receive daily supplements of at
least 500 mg calcium and at least 400 IU of vitamin D, unless hypercalcemia is
documented .

IV injections (Zometa or placebo): every 4 weeks, SC injections (Denosumab or
placebo): every 4 weeks, Total skeletal X-rays: every 12 weeks, Blood sampling
at screening and every 4 weeks. See also protocol version 07 March 2006 p. 74.

There could be allergic reactions to the s.c injections and iv administering of
the medication.
The blood sampling can cause bruising and pain.

Known adverse events of denosumab are temporary decrease in blood calcium
levels with symptoms of tingling sensation or muscle cramping.
Fatigue, muscle stiffness, weakness, bone pain constipation, upper respiratory
inflammation or pain, diarrhea, abnormal touch sensation or itching or redness
of the skin.
Infrequently development of antibodies to denosumab has occured.

Zoledronic acid: Adverse events reported by patients using intravenous
bisphosphonates include (but are not limited to) the following: fever, nausea,
constipation, diarrhea, vomiting, abdominal pain, bone and muscle pain, anemia
(low red blood cell counts), fatigue, cough, difficulty breathing, weakness,
and swelling of lower limbs.
Damage to the jaw bone (also called osteonecrosis of the jaw or ONJ) has been
reported in patients with cancer receiving treatment regimens that include
bisphosphonates.

The benefit for subjects is that all will be treated by an active drug shown to
be effective in regards to delaying or preventing SRE occurance .