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 men with hormone-refractory prostate cancer and bone metastases.
ID
Source
Brief title
Condition
- Bone disorders (excl congenital and fractures)
- Reproductive and genitourinary neoplasms gender unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time to the first on-study SRE (non-inferiority)
Secondary outcome
Time to the first on-study SRE (superiority)
Time to the first-and-subsequent on-study SRE (superiority, using multiple
event analysis)
Subject incidence of treatment-emergent adverse events
Changes in laboratory values
Incidence of anti-denosumab antibody (binding and neutralizing) formation
Background summary
Prostate cancer constitutes the second most common cause of cancer-related
death in men from Western industrialized countries. In these patients, bone
metastases are a frequent fidning. 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. In this study, Denosumab (a monoclonal antibody)
will be compared to Zoledronic Acid (a bisphosphonate).There is previous
clinical experience with Denosumab in the treatment of 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
men with hormone-refractory prostate cancer and bone metastases.
Study design
Approximately 1780 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 an 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 p. 72-75.
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
p. 76.
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
CA 91320, Thousand Oakes
US
One Amgen Center Drive
CA 91320, Thousand Oakes
US
Listed location countries
Age
Inclusion criteria
- Men >= 18 years of age with histologically-confirmed prostate cancer;- Current or prior radiographic (ie, x-ray, computer tomography [CT], or magnetic resonance imaging [MRI]) evidence of at least 1 bone metastasis;- Documented failure of at least one hormonal therapy as evidenced by a rising PSA (ie, 3 consecutive determinations, taken at least 2 weeks apart from one another. The third measurement must be >= 0.4 ng/mL and be taken within 8 weeks prior to randomization) ;- Serum testosterone level of < 50 ng/dL due to either surgical or chemical castration ;- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2;- Adequate organ function as defined by the following criteria:
-aspartate aminotransferase (AST) <= 5 x upper limit of normal (ULN)
-alanine aminotransferase (ALT) <= 5 x ULN
-total bilirubin <= 2 x ULN
-creatinine clearance (Cockcroft-Gault) >=30 mL/min
-albumin-adjusted serum calcium >= 2.0 mmol/L (8.0 mg/dL) and <= 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
- Current or prior IV bisphosphonate administration for any reason ;- Current or prior oral bisphosphonate administration 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(s) for the course of the study;- Evidence of any of the following conditions per subject self report or medical chart review:
-known history of second malignancy within the past 3 years, except for basal cell carcinoma
-known infection with human immunodeficiency virus
-active infection with hepatitis B or hepatitis C virus;- Any 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 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 | EUCTR2006-000341-19-NL |
| CCMO | NL11590.098.06 |