To determine if denosumab is non-inferior to zoledronic acid (Zometa) with respect to the first on-study occurrence of a skeletal-related event (SRE) in subjects with advanced breast cancer and bone metastases.
ID
Source
Brief title
Condition
- Bone disorders (excl congenital and fractures)
- Skeletal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time to the first on-study SRE (non-inferiority)
Secondary outcome
Secondary Efficacy Endpoints
* time to the first on-study SRE (superiority)
* time to the first-and-subsequent on-study SRE (superiority, using multiple
event analysis)
Safety Endpoints
* subject incidence of treatment-emergent adverse events
* changes in laboratory values
* Incidence of anti-denosumab antibody (binding and neutralizing) formation
Background summary
Worldwide, there were approximately 1,150,000 cases of breast cancer reported
in 2002 with 411,000 deaths. 75% of metastatic breast cancer patients will
develop bone metastases. Over 50% of all breast cancer patients with bone
metastases exhibit pathologic fractures. 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.
Study objective
To determine if denosumab is non-inferior to zoledronic acid (Zometa) with
respect to the first on-study occurrence of a skeletal-related event (SRE) in
subjects with advanced breast cancer and bone metastases.
Study design
Approximately 1690 subjects will be randomized in a 1:1 ratio to receive either
denosumab, administered at a dose of 120 mg subcutaneously (SC) every 4 weeks
(Q4W), or zoledronic acid administered intravenously (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 at least one on-study SRE and the
primary efficacy and safety analysis is completed. 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 documented
hypercalcemia.
If Denosumab is determined to have an positive benefit:risk profile compared
with zoledronic acid, all subjects currently undergoing every 4 weeks scheduled
assessments will be offered open-label denosumab at a dose of 120 mg SC until
subjects have access to commercially available product or for up to 2 years,
which ever comes first. If benfit:risk profile is not positive, all subjects
will be followed for survival for 2 years after the last dose of blinded IP.
Intervention
IV injections (Zometa or placebo): every 4 weeks, SC injections: Denosumab or
placebo: every 4 weeks, Totally skeletal X-rays: every 12 weeks, Blood sampling
at screening and every 4 weeks. See also protocol version 30 April 2008 p.
80-82.
Open-label phase: SC injections Denosumab every 4 weeks, Blood sampling every 4
weeks during the first 3 months, subsequently every 12 weeks. See also protocol
version 30 April 2008 p. 83.
Study burden and risks
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.
Fatique, 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 .
One Amgen Center Drive, Thousand Oaks, CA
CA 91320
US
One Amgen Center Drive, Thousand Oaks, CA
CA 91320
US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria:
* adult (men included) with histologically or cytologically confirmed breast adenocarcinoma
* current or prior radiographic (ie, x-ray, computer tomography [CT], or magnetic resonance imaging [MRI]) evidence of at least 1 bone metastasis
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
* adequate organ function as defined by the following criteria:
* serum aspartate aminotransferase (AST) less than or equal to 5 x upper limit of normal (ULN)
* serum alanine aminotransferase (ALT) less than or equal to 5 x ULN
* serum total bilirubin less than or equal to 2 x ULN
* creatinine clearance (Cockcroft-Gault) equal or higher to 30 mL/min
* albumin-adjusted serum calcium equal or higher to 2.0 mmol/L (8.0 mg/dL) and less than or equal to 2.9 mmol/L (11.5 mg/dL)
* Before any study-specific procedure is performed, the appropriate written informed consent must be obtained.
Exclusion criteria
Exclusion Criteria:
* current or prior IV bisphosphonate administration
* current or prior oral bisphosphonate for the treatment of bone metastasis
* planned radiation therapy or surgery to bone
* prior administration of denosumab
* known brain metastases
* life expectancy less than 6 months
* prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
* active dental or jaw condition that requires oral surgery
* non-healed dental/oral surgery
* planned invasive dental procedure over the course of the study
* evidence of any of the following conditions per subject self report or medical chart review:
* any prior malignancy (other than breast cancer, basal cell carcinoma or in situ cervical cancer) with active disease within 3 years before randomization
* known infection with human immunodeficiency virus
* active infection with Hepatitis B virus or Hepatitis C virus
* any organic or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
* thirty days or less since receiving an investigational product or device (ie, does not have marketing authorization) in another clinical trial
* subject with reproductive potential who will not agree to use effective contraception (as defined by the principal investigator or designee)
* known sensitivity to any of the products to be administered during the study (eg, zoledronic acid, mammalian derived products, calcium or vitamin D)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-000339-93-NL |
| CCMO | NL11609.098.06 |