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Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Swiss Group for Clinical Cancer Research
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier:
NCT02051218
First received: January 29, 2014
Last updated: September 9, 2014
Last verified: September 2014

January 29, 2014
September 9, 2014
July 2014
December 2019   (final data collection date for primary outcome measure)
Time to first on-trial symptomatic skeletal event (SSE; Clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
A SSE is defined as one of the following events: Clinically significant pathological fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.
Same as current
Complete list of historical versions of study NCT02051218 on ClinicalTrials.gov Archive Site
  • Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: Yes ]
  • Time to first and subsequent on-trial SSE [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Quality of Life [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Skeletal morbidity period rate (SMPR) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Skeletal morbidity rate (SMR) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Health economic analysis [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Bone turnover marker change [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Overall Survival (OS) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks
Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial

The aim of the trial is to test the hypothesis that the benefit of denosumab is maintained if administered only every 12 weeks as compared to every 4 weeks.

Denosumab, a monoclonal antibody against RANK-Ligand has been shown superior to zoledronic acid in delaying time to a first on-study skeletal related event (SRE) in patients with solid tumors, with no effects on disease progression or survival. Many SREs were silent compression fractures found only because of scheduled imaging. The approved dose of denosumab is 120 mg s.c. every 4 weeks (q4w). Although generally well tolerated, there is a time-dependent increase in osteonecrosis of the jaw in up to 8% of patients. Cases of fatal hypocalcaemia were observed during post marketing surveillance.

The optimal dose and schedule for denosumab is unknown. Denosumab is associated with considerable costs and may add toxicity; thus a study of de-escalation is warranted.

The aim of the trial is to test the hypothesis that the benefit of Denosumab is maintained if administered 120 mg q12w as compared to 120 mg q4w. The primary endpoint of this open-label randomized phase III non-inferiority trial is time to first on-trial symptomatic skeletal event (SSE: i.e. clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). With a non-inferiority margin of 1.2 for the hazard ratio, a power 80% and a type I error 5%, the total sample size is 1380. Secondary endpoints are safety, time to subsequent on-trial SSE, quality of life, health economic outcomes, and change in bone turnover markers. This study is open for international collaboration.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Supportive Care
  • Metastatic Breast Cancer
  • Metastatic Prostate Cancer
  • Bone Metastases
  • Drug: Denosumab (reduced dosing)
    3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
    Other Name: XGEVA®
  • Drug: Denosumab (standard dosing)
    Denosumab 120mg (XGEVA®) sc. q4w
    Other Name: XGEVA®
  • Active Comparator: Arm A (standard arm)
    Denosumab 120mg (XGEVA®) sc. q4w
    Intervention: Drug: Denosumab (standard dosing)
  • Experimental: Arm B (reduced arm)
    3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
    Intervention: Drug: Denosumab (reduced dosing)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1380
December 2022
December 2019   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patient has given written informed consent.
  • Histologically confirmed diagnosis of breast or prostate cancer before randomization.
  • Patient has metastatic breast cancer (stage IV, all subtypes allowed) or prostate cancer (stage IV) and bone metastases and is planned to receive or is receiving antineoplastic treatment.
  • Patients with prostate cancer must have evidence of disease progression on continuous androgen deprivation therapy (CRPC).
  • Patients must have ≥ 3 bone metastases (lytic or blastic or mixed). The lesions must be documented by radiological evaluation within 12 weeks before randomization (by X-Ray, CT scan, PET-CT, MRI scan or bone scintigraphy).
  • WHO performance status 0-2
  • Age ≥ 18 years.
  • Corrected serum calcium ≥ 2 mmol/l and ≤ 3 mmol/l (medical treatments to obtain serum calcium levels in the normal range are allowed, as far as no bisphosphonates or denosumab are used).
  • Liver transaminases within normal range or not more than 3 x ULN with liver metastases. Serum total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in case of known Gilbert's disease)
  • Women are not breastfeeding. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential.
  • Men agree not to father a child during participation in the trial and during 12 months thereafter.

Exclusion Criteria:

  • Definite contraindication for denosumab (e.g. hypocalcaemia [Albumin-corrected serum calcium < 2.0 mmol/l]).
  • History or current evidence of osteonecrosis of the jaw.
  • Non-healed mucosa in oral cavity (by surgery or as a side effect of any other treatment).
  • Jaw or dental conditions that require oral surgery or if surgery or invasive dental procedures are planned.
  • Prior use of denosumab for bone metastases (dose 120 mg every 4 weeks) or bisphosphonates to treat bone metastases. Patients treated with denosumab or bisphosphonates against osteopenia or osteoporosis are allowed to enter the trial if the last dose was more than 28 days before randomization.
  • Patients with known osteoporosis (T-score ≤ -2.5) at study entry (since fractures from osteoporosis are difficult to be discriminated from fractures through bone metastases).
  • Radiotherapy or surgery to the bone within the last two weeks before randomization or planned within 6 weeks after randomization.
  • Presence or history of CNS metastases or leptomeningeal disease. A MRI evaluation within 12 weeks before randomization must be performed in case of suspicious symptoms.
  • Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling out QoL forms.
  • Concurrent treatment in a clinical trial with SSE or SRE as primary endpoint.
  • Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose).
  • Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol.
Both
18 Years and older
No
Contact: Lukas Stalder, PhD +41 31 389 91 99 lukas.stalder@sakk.ch
Switzerland
 
NCT02051218
SAKK 96/12
No
Swiss Group for Clinical Cancer Research
Swiss Group for Clinical Cancer Research
Not Provided
Study Chair: Roger von Moos, PD MD Kantonsspital Graubünden
Study Chair: Arnoud Templeton, MD Cantonal Hospital of St. Gallen
Study Chair: Silke Gillessen, Prof Cantonal Hospital of St. Gallen
Study Chair: Andreas Müller, MD Kantonsspital Winterthur KSW
Swiss Group for Clinical Cancer Research
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP