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

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ClinicalTrials.gov Identifier: NCT02051218
Recruitment Status : Recruiting
First Posted : January 31, 2014
Last Update Posted : April 6, 2020
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

Tracking Information
First Submitted Date  ICMJE January 29, 2014
First Posted Date  ICMJE January 31, 2014
Last Update Posted Date April 6, 2020
Actual Study Start Date  ICMJE July 16, 2014
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2014)
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. ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2018)
  • Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw) [ Time Frame: at the latest 5 years after randomization. ]
  • Time to first and subsequent on-trial SSE [ Time Frame: at the latest 5 years after randomization. ]
  • Quality of Life measured by FACT-G and FACT-BP [ Time Frame: at the latest 5 years after randomization. ]
  • Skeletal morbidity period rate (SMPR) [ Time Frame: at the latest 5 years after randomization. ]
  • Skeletal morbidity rate (SMR) [ Time Frame: at the latest 5 years after randomization. ]
  • Health economic analysis [ Time Frame: at the latest 5 years after randomization. ]
  • Bone turnover markers [ Time Frame: at the latest 5 years after randomization. ]
  • Overall Survival (OS) [ Time Frame: at the latest 5 years after randomization. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2014)
  • Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw) [ Time Frame: at the latest 5 years after randomization. ]
  • Time to first and subsequent on-trial SSE [ Time Frame: at the latest 5 years after randomization. ]
  • Quality of Life [ Time Frame: at the latest 5 years after randomization. ]
  • Skeletal morbidity period rate (SMPR) [ Time Frame: at the latest 5 years after randomization. ]
  • Skeletal morbidity rate (SMR) [ Time Frame: at the latest 5 years after randomization. ]
  • Health economic analysis [ Time Frame: at the latest 5 years after randomization. ]
  • Bone turnover marker change [ Time Frame: at the latest 5 years after randomization. ]
  • Overall Survival (OS) [ Time Frame: at the latest 5 years after randomization. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks
Official Title  ICMJE Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Metastatic Breast Cancer
  • Metastatic Prostate Cancer
  • Bone Metastases
Intervention  ICMJE
  • 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®
Study Arms  ICMJE
  • Active Comparator: Arm A (standard arm)
    Denosumab 120mg (XGEVA®) sc. q4w
    Intervention: Drug: Denosumab (standard dosing)
  • Experimental: Arm B (reduced arm)
    Denosumab 120mg (XGEVA®) sc. q4w [weeks 1, 5, 9] followed by Denosumab 120mg (XGEVA®) sc. q12w [weeks 13, 25, …]
    Intervention: Drug: Denosumab (reduced dosing)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 29, 2014)
1380
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 denosumab is used. Maximally 1 dose of bisphosphonates in the case of hypercalcemia is allowed, if the bisphosphonate was applied at least 3 weeks before the first dose of denosumab).
  • Liver transaminases not more than 1.5 x ULN 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Corinne Schär, PhD +41 31 389 91 91 trials@sakk.ch
Listed Location Countries  ICMJE Austria,   Germany,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02051218
Other Study ID Numbers  ICMJE SAKK 96/12
000000685 ( Other Identifier: SNCTP )
2014-001189-87 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Swiss Group for Clinical Cancer Research
Study Sponsor  ICMJE Swiss Group for Clinical Cancer Research
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Swiss Group for Clinical Cancer Research
Verification Date March 2020

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